Pharmacology of ccf

Drugs used in management of CCF

1. Autacoids Angiotensin Kinins CCF 12/27/2018 1 PATKI PHARMACOLOGY OF CCF

2. AT the end of the two sessions, students should be able to Derive the signs and symptoms of Cardiac failure Enumerate drugs used in CCF Describe the mechanism of action of Digoxin in CCF. Describe the role of vasodilators, Diuretics CCBs, ACE inhibitors in CCF, Describe management of Chronic heart failure and Acute congestive cardiac failure. 12/27/2018 2 PATKI

3. Heart Failure Click to open ! Heart Failure- Clinical syndrome … can result from any structural or functional cardiac disorder that impairs ability of ventricle to fill with or eject blood Impact! 5 million - have heart failure 500,000 new cases every year 25-50 billion dollars a year to care for people with HF 6,500,000 hospital days / year and 300,000 deaths/year 12/27/2018 3 PATKI

4. Definition-Heart Failure (HF) Key Concepts CO = SV x HR-becomes insufficient to meet metabolic needs of body SV- determined by preload, afterload and myocardial contractility EF< 40% (need to understand) * Classifications HF Systolic failure- dec. contractility Diastolic failure- dec. filling Mixed 12/27/2018 4 PATKI

5. 90/140= 64% EF- 55-65 (75) normal Click for animated EF 12/27/2018 5 PATKI

6. Heart Failure Etiology and Pathophysiology Systolic failure- most common cause Hallmark finding: Dec. in * left ventricular ejection fraction (EF) Due to Impaired contractile function (e.g., MI) Increased afterload (e.g., hypertension) Cardiomyopathy Mechanical abnormalities (e.g., valve disease) 12/27/2018 6 PATKI

7. Heart Failure Etiology and Pathophysiology Diastolic failure Impaired ability of ventricles to relax and fill during diastole > dec. stroke volume and CO Diagnosis based on presence of pulmonary congestion, pulmonary hypertension , ventricular hypertrophy * normal ejection fraction (EF)- Know why! 12/27/2018 7 PATKI

8. Heart Failure Etiology and Pathophysiology Mixed systolic and diastolic failure Seen in disease states such as dilated cardiomyopathy (DCM) Poor EFs (<35%) High pulmonary pressures Biventricular failure (both ventricles may be dilated and have poor filling and emptying capacity) 12/27/2018 8 PATKI

9. Preload Volume of blood in ventricles at end diastole Depends on venous return Depends on compliance Afterload Force needed to eject blood into circulation Arterial B/P, pulmonary artery pressure Valvular disease increases afterload Factors effecting heart pump effectiveness 12/27/2018 9 PATKI

10. Cardiomegaly/ventricular remodeling occurs as heart overworked> changes in size, shape, and function of heart after injury to left ventricle . Injury due to acute myocardial infarction or due to causes that inc. pressure or volume overload as in Heart failure 12/27/2018 10 PATKI

11. Right Heart Failure Signs and Symptoms fatigue, weakness, lethargy wt. gain, inc. abd . girth, anorexia, pain elevated neck veins Hepatomegaly may not see signs of LVF 12/27/2018 11 PATKI

12. What does this show? 12/27/2018 12 PATKI

13. What is present in this extremity, common to right sided HF? 12/27/2018 13 PATKI

14. Heart Failure Low output cardiac failure – CO is low and it is common HF where metabolic demands of the body are within normal limits High output cardiac failure occurs rarely – hyperthyroidism, severe anaemia and A-V shunt where metabolic demands of the body are excessive that even ↑ CO is insufficient to meet them – treatment correct the underlying cause 12/27/2018 14 PATKI

15. Compensatory physiological responses in CHF Increased sympathetic activity – initially ↑CO - ↑ preload and ↑ afterload finally ↓ CO Activation of Renin- Angiotension-Aldosterone system(RAAS) - ↑in blood volume ↑ preload and also ↑ afterload . Atrial stretch releases ANP(atrial natriuretic peptide) Ventricular Remodeling –↑end diastolic M. fibre length – initially maintains cardiac performance – later ventricular wall tension ↑ - ventricular dilatation and mechanical performance of heart ↓ Ventricular hypertrophy, myocardial cell apoptosis, fibrotic change in myocardium With the compensatory mechanisms – adequate CO- HF said to be compensated HF Adoptive mechanisms fails to maintain CO – decompensated HF 12/27/2018 15 PATKI

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17. Signs and symptoms of HF Pulmonary and peripheral oedema Dyspnoea and cyanosis Hepatomegaly Cardiomegaly Reflex tachycardia Decreased urine output Muscle fatigue and ↓ exercise tolerance 12/27/2018 17 PATKI

18. Various classes of drugs in different stages of heart failure 12/27/2018 18 PATKI

19. Treatment of CHF The goals of treatment are Relieve the symptoms of disease Prevent disease progression Prolong survival Therapeutic strategies in CHF Role of drugs Vasodilators – which reduce excessive preload (volume of blood that fills the ventricle during diastole (venous return) and afterload (the pressure that must be overcome for the heart to pump blood into the arterial system Diuretics – ↓volume load and improve ventricular efficiency Remove peripheral edema and pulmonary congestion Positive inotropic agents - ↑ CO Drugs to be avoided – NSAID’s, verapamil , plasma expanders 12/27/2018 19 PATKI

20. Treatment of CHF There are two distinct goals of drug therapy in CHF a) Relief of congestive/low output symptoms and restoration of cardiac performance Inotropic drugs – digoxin, Dobutamine/dopamine, amrinone / milrinone Diuretics – Furosemide, thiazides Vasodilators – ACE inhibitors / AT1 antagonists, hydralazine, nitrate, nitroprusside β blockers – metoprolol, bisoprolol, carvedilol b) Arrest/reversal of disease progression and prolongation of survival ACE inhibitors / AT1 antagonists (ARB’s) β blockers Aldosterone antagonist - Spironolactone c) Salt restriction, rest and treatment of underlying cause of CHF 12/27/2018 20 PATKI

21. Treatment of CHF High ceiling diuretics – Furosemide, bumetonide with Spironolactone ↓ preload and improve ventricular efficiency by reducing vol. load Remove pulmonary congestion and peripheral edema don't influence the primary disease process in CHF chronic diuretic therapy –hypokalemia may ↑ digitalis toxicity They may cause activation of renin- angiotensin system diuretics should be combined ACEI/digoxin (improves LV function) 12/27/2018 21 PATKI

22. Treatment of CHF Vasodilators Venodilators (primarily ↓preload) GTN, Isosorbide dinitrate Arteriolar dilator s (primarily ↓afterload) Hydralazine, Minoxidil, CCB-Nifedipine, K chanel opener- Nicorandil Mixed dilators ( ↓pre and after load) ACE Inhibitors, AT1 antagonists (ARBs), Prazosin ( α 1 blocker), Amrinone , Milrinone, Nitroprusside They have become the mainstay of anti-CHF measures Used IV in acute HF Orally for long term therapy for chronic CHF Arteriolar dilators cause reflex tachycardia and fluid retention 12/27/2018 22 PATKI

23. ACE Inhibitors / ARBs Agent of choice in CHF and superior to other vasodilators ↓ circulating levels of Angiotensin II ↓ rate of bradykinin inactivation - ↑bradykinin – vasodilatation ↓ secretion of aldosterone - ↓ sodium and water retention ↓ preload and after load ↓ Ang II direct toxic effect (↓ risk of coronary ischemic events) Afford symptomatic / disease modifying benefits by retarding ventricular hypertrophy, myocyte apoptosis. Spironolactone + ACEI – beneficial further reduces mortality low dose 12.5 – 25mg/day (to avoid hyperkalemia ) 12/27/2018 23 PATKI

24. Uses All grades of CHF - if renal impairment – replace with hydralazine Left ventricular enlargement CHF in asymptomatic patients with ejection fraction < 40% Immediately after MI Dose Start with small dose enalapril /ramipril-2.5mg, (max10/5mg) bid ARBs – Losartan/ candesartan (block AT1 receptor on heart, vessel and kidney) Used in patients who can’t tolerate ACEI because of dry cough, angioedema, neutropenia 12/27/2018 24 PATKI

25. β 1 blockers - Metoprolol, bisoprolol Β blocker – Carvedilol ISE Long term R improves symptoms, ↓ hospitalization, ↓ mortality Always given in combination with ACEI +diuretic/digitalis It antagonizes excess sympathetic activity in CHF that enhances ventricular wall stress Used (unless contraindicated) in mild to moderate cases of dilated cardiomyopathy with systolic dysfunction Starting dose should be very low – gradually ↑(carvedilol-3.125mg -25mg, metoprolol – 25mg-<200mg, bisoprolol-2.5mg-10mg/day They are not indicated in – Decompensated HF/ Acute HF after acute MI HR-< 60/min, asthma, COPD 12/27/2018 25 PATKI

26. Sympathomimetic inotropic drugs – Dobutamine, dopamine, amrinone, milrinone 12/27/2018 26 PATKI

27. Dobutamine - acts on β 1, β 2 and α 1 receptors Selective β 1 – Inotropic action ↑- CO Little effect on BP / HR (counterbalance of β 2 and α 1) Used for short term management of acute HF with MI - IV infusion (5-15 μ g/kg/min)in acute HF with MI/cardiac surgery Dopamine - in moderate dose (5-10 μ g/kg/min) β 1 – Inotropic action ↑- CO TPR – unchanged due to renal and splanchnic vasodilatation (D1) Higher dose ↑ TPR and ↑ afterload Used in acute HF with renal impairment Due to development of tolerance - no role in the long term management of CHF 12/27/2018 27 PATKI

28. Amrinone – phosphodiesterase inhibitor ↑ myocardial cAMP and -↑transmembrane influx of Ca++ +ve inotropic and direct vasodilator action – INODILATOR ↑ LVEF and ↓ left ventricular end diastolic volume Used for short term R of severe HF – administered IV 0.5mg/kg bolus followed by 5-10 μ g/kg/min IV infusion A/E – nausea, diarrhoea, fever, hepatotoxicity, arrhythmias, thrombocytopenia 12/27/2018 28 PATKI

29. Milrinone - phosphodiesterase inhibitor More potent than amrinone Shorter acting (t1/2 40-80 min) Used for short term R of severe HF – administered IV 50 μ g/kg bolus followed by 0.4-1.0 μ g/kg/min IV infusion Nisiritide Synthetic form of the endogenous peptide Brain Natriuretic Peptide ↑ cGMP in vascular smooth muscle - ↓ pre & afterload ↑ salt and water excretion Used IV – to relieve dyspnoea & other symptoms in refractory CHF 2mg/kg bolus followed by 0.01-0.03 μ g/kg/min IV infusion 12/27/2018 29 PATKI

30. Cardiac Glycosides 12/27/2018 30 PATKI

31. Cardiac Glycosides Digitalis purpurea (Fox glove) aglycone Seeds of strophanthus gratus Strophanthin-G & Ouabain 12/27/2018 31 PATKI

32. MOA of cardiac glycosides 12/27/2018 32 PATKI

33. MOA of cardiac glycosides 12/27/2018 33 PATKI RYANODINE RECEPTOR

34. MOA of cardiac glycosides ↑ Na+ alters the driving force (↓ transmembrane gradient of Na+ which drives the extrusion of Ca2+) for Na-Ca exchange by the exchanger (NCX) – so that less Ca2+ is removed from the cell In ANS, inhibit sympathetic outflow and ↑ vagal tone At AV node prolong ERP and slow CV ↑ serum K+ inhibits digitalis binding to Na/K ATPase (Hypokalemia↑ risk of digit toxicity) 12/27/2018 34 PATKI

35. Pharmacological actions of digitalis Cardiac Extra cardiac Cardiac actions – (more prominent in failing heart) Direct action on the heart (by inhibiting Na + / K + ATPase) and Indirect actions on the heart by stimulating Vagus (vagomimetic) Myocardial contractility → +ve Inotropic effect – “Cardiotonic” ↑ Force of contraction of the myocardium (more prominent in failing heart) Digitalized heart contracts more forcibly and completely This causes complete emptying of the ventricles during systole and ↑ CO This ↓ pulmonary congestion and systemic venous pressure Diastolic size of the heart is reduced – size of the muscle fibre length also reduced ↓ oxygen requirement of myocardium The digitalized heart, thus, can do more work for the same energy expenditure 12/27/2018 35 PATKI

36. Heart rate – causes bradycardia (more marked in CHF patients) Reduces HR (-ve chronotropic effect) by direct and indirect action (small dose) Extravagal – direct depressant action on SA and AV nodes Electrophysiological properties – differs with the cardiac fibres Action Potential – RMP progressively ↓ Excitability ↑ at low doses (↓ gap between RMP & TP) but depressed at toxic dose The slope of phase 4 depolzn ↑ in PFs & ventricular muscle – ectopic automcity. Results in ventricular extra systoles, Coupled beats (due to delayed after d) ERP – ↑ at AV node & bundle of His 12/27/2018 36 PATKI

37. Conduction velocity Conduction through AV node depressed (by both action) ECG ↑ PR interval (slowing of AV conduction) AV block at toxic doses Shortening of QT interval (reflecting shortening of systole) Depression of ST segment (at high doses due to interference Ĉ repolarzn ) 12/27/2018 37 PATKI

38. Blood vessels – digitalis has mild direct vasoconstrictor action – not significant Extra cardiac actions Kidney – digitalis causes diuresis in CHF secondary to improvement in circulation and renal perfusion (no diuresis in patients with edema due to other causes) CNS - in high doses – CTZ activation – vomiting, central sympathetic stimulation, confusion, disorientation, blurring of vision GIT – Anorexia, nausea, vomiting (CTZ stimulation and direct action on the gut) 12/27/2018 38 PATKI

39. Pharmacokinetics Digoxin / Digitoxin commonly used glycoside – administered by oral route food delays the absorption, widely distributed, concentrated in heart, liver, kidney and skeletal muscle crosses BBB mainly excreted unchanged in urine (digoxin- filtered at the glomeruli) (dose adjust-renal fail) Cardiac glycosides are cumulative drugs Steady state levels and full therapeutic effect with daily maintenance from the beginning are attained after 6-7 days for digoxin and 4 weeks for digitoxin (after 4xt 1/2 ) Preparations Digoxin – 0.25mg tab, 0.5mg/2ml inj 0.05mg/ml paediatric elixir Used for routine and in emergency Digitoxin – 0.1mg tab Used for maintenance (long t 1/2 ) 12/27/2018 39 PATKI

40. Adverse effects Toxicity of digitalis is high – margin of safety is low (Therapeutic Index is 1.5 - 3) Extra cardiac A/E Anorexia, nausea, vomiting, fatigue, mental confusion, restlessness, psychosis, visual disturbances, diarrhoea, skin rashes, gynecomastia(rare) Cardiac A/E Bradycardia, partial/complete heart block, coupled beats (bigeminy), ventricular extrasystoles/tachycardia/fibrillation, atrial extrasystoles, AF Factors affecting digitalis toxicity Age, IV digitalization, hypokalemia, hypercalcaemia, hypomagnesaemia, Hyper/hypothyroidism, renal failure, myocarditis (predisposing factors) 12/27/2018 40 PATKI

41. Management of digitalis toxicity Potassium supplementation – mild toxicity KCl 5gm daily oral tid More serious arrhythmias - IV infusion KCl 20m.mol/hr Stop digoxin and K depleting diuretics Supraventricular arrhythmias – treated with oral/IV propranolal Ventricular arrhythmias – Lignocaine IV (suppresses excessive automaticity and doesn't accentuate AV block) AV block and bradycardia – Atropine 0.6 – 1.2mg im /cardiac pacing 12/27/2018 41 PATKI

42. Digoxin antibodies (Digibind) Used in serious digitalis toxicity It neutralizes circulating digitalis - given IV - rapidly reverses the toxicity (40mg neutralises 0.6mg of digoxin stored in the body) But very expensive 12/27/2018 42 PATKI

43. Contraindications Hypokalemia Elderly, associated disease like renal/hepatic disease MI except when HF with AF and rapid ventricular rate Hyper / hypothyroidism (slow elimination) Partial AV block Myocarditis (more prone to arrhythmias) Wolff-Parkinson-White syndrome – Digitalis may enhance transmission through bypass tract and ↑ transmission of rapid atrial impulses to ventricles - VF 12/27/2018 43 PATKI

44. Drug interactions 12/27/2018 44 PATKI

45. Therapeutic Uses Congestive Heart Failure To control ventricular rate in AF/ AFl Low output failure especially when associated with AF. It is ineffective in high output failure – severe anaemia, thyrotoxicosis and A-V shunt Subsides pulmonary congestion – provides relief from dyspnoea ↑ Urinary output- ↓ edematous fluid by ↑ing renal perfusion Engorged tender liver regresses and engorgement of neck veins disappear because of diminished systemic venous pressure Mild to moderate cases – slow digitalization Digoxin 0.125-0.25mg/day from the beginning (maintenance dose) Relief of signs and symptoms like ↓HR, bradycardia(HR<60 stop drug) 12/27/2018 45 PATKI

46. Therapeutic Uses Rapid oral digitalization – Digoxin 0.5mg – 1mg stat, followed by 0.25mg every 6 hrs till response occurs (6-24 hrs) – seldom practised Emergent IV digitalization – Digoxin 0.25mg followed by 1mg hrly slow IV injection with close monitoring till response occurs(2-6hrs) (total dose 0.5mg-1mg) – rarely practised Digitalis still most effective drug, especially in patients with dilated heart and low ejection fraction (systolic dysfunction) Mild to moderate cases can be managed without digitalis – with diuretics , vasodilators (like ACE inhibitor) and β blockers. 12/27/2018 46 PATKI

47. Therapeutic Uses Cardiac arrhythmias Atrial Fibrillation (500 beats/min) To control ventricular rate – protects the ventricles from the too rapid atrial impulses by depressing AV conduction Ventricular rate of 70-80 not achieved – verapamil / β blockers may be added Atrial flutter (AFl) (200-300 beats/min) regular and homogenous AFl is often converted to AF and withdrawal of digoxin at this stage may restore normal rhythm (since the cause of atrial inhomogeneity is gone) PSVT (150 – 200/min and 1:1 AV conduction) PSVT with HF - ↑ vagal tone and terminates arrhythmia. Verapamil, adenosine –more effective, act faster and less toxic. 12/27/2018 47 PATKI

48. Management of acute LVF with pulmonary edema Semi-upright posture Oxygen 6-8litres/min Furosemide 40-80mg IV– Repeated every 30 min Morphine IV 2-5mg IV Aminophylline IV slowly 250-500mg Sublingual 0.4mg rpt every 15 min if required /IV Nitroglycerine Digoxin IV 0.5mg – associated with AF/SVT 12/27/2018 48 PATKI

49. Goals of Treatment- ADHF/Pulmonary Edema) MAD DOG Improve gas exchange Start O2/elevate HOB/ intubate M orphine – dec anxiety/ afterload A- (airway/head up/legs down) AMINOPHYLLINE D- (Drugs) Dig not first now- but drugs as IV nitroglycerin; IV D- Diuretics O- oxygen /measure sats ; Hemodynamics , careful observation G- blood gases 12/27/2018 49 PATKI

50. TERIMA KASIH Thank you 12/27/2018 50 PATKI kegagalan jantung