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Drugs for congestive heart failure
- 2. Heart Failure inability of the heart to supply sufficient blood flow to meet the needs of the body
- 3. LV Dysfunction Systolic Dysfunction Diastolic Dysfunction inability of the heart to supply sufficient blood flow
- 4. LV Dysfunction Decreased cardiac output RAAS activation Sympathetic activation Increased cardiac output (via increased contractility and heart rate) Increased blood pressure (via vasoconstriction and increased blood volume) Salt and water retention Increased cardiac workload (increased preload and afterload) Vicious Cycle of Heart Failure Pathophysiology of HF Left ventricular dysfunction
- 5. Pathophysiology of HF Left ventricular dysfunction Left ventricular dysfunction Compensatory mechanisms -RAAS activation -Sympathetic system activation -Vicious cycle Ischemic heart disease Cigarette smoking Hypertension Obesity Diabetes Valvular heart disease
- 7. Cardiac performance is a function of 4 primary factors Preload Afterload Contractility Heart rate In CHF ↑ ↑ ↓ ↑
- 8. LV remodeling changes in size, shape, and function of the heart after injury to the ventricles -- implies a decline in function of heart Angiotensin II Aldosterone Sympathetic stimulation ↑after load , fluid & Na+ retention ↑ expression of growth factors ↑synthesis of extracellular matrix Hypertrophy of myocytes ACE inhibitors ,ARBs β blockers Spironolactone Improve survival ↓ mortality
- 10. STAGE DISABILITY CLASS 1 MILD No symptoms - Can perform ordinary activities without any limitations CLASS 2 MILD Mild symptoms - Somewhat limited in ability to exercise or do other strenuous activities CLASS 3 MODERATE Noticeable limitations in ability to exercise Comfortable only at rest CLASS 4 SEVERE Unable to do any physical activity without discomfort Some HF symptoms at rest 10 NYHA classification = New York Heart Association
- 11. Goal of treatment • 1) Relief of congestive/low output symptoms, restoration of cardiac performance and treatment of acute decompensation • lnotropic drugs- Digoxin, dobutamine/ dopamine, inamrinone/milrinone • Diurerics-Furosemide, thiazides, metolazone • RAS inhibitrs- ACE inhibitors/ARBs • Vasodilators- Hydralazine, nitrate, nitroprusside • Symhetic BNP-Nesiritide • beta blocker- Metoprolol, bisoprolol, carvedilol, nebivolol
- 12. • 2) Arrest/reversal of disease progression and prolongation of survival • ACE inhibitors/ ARBs • beta blockers • Aldosterone antagonist-Spironolactone, eplerenone • Neprilysin inhihiror- Sacubitril
- 13. ACE inhibitors / ARBs Hemodynamic benefits ↓ preload & afterload ↓ Pulmonary capillary wedge pressure Exercise capacity ↑ reverse ventricular remodeling prevents or delays the progression of heart failure Drug of choice
- 14. Drugs = β blockers •Decreasing the frequency of unstable tachyarrhythmias •antagonism of ventricular wall stress enhancing, apoptosis promoting and pathological remodeling effects- Through inhibition of sustained sympathetic nervous system activation •Used in NYHA class 2/3 •no place for beta blockers in decompensate patients •Should be combined with ACEI / ARBs •Start with low dose ----- titrated to target dose Metoprolol Carvidilol Bisoprolol CHF patients are prone to arrhythmias
- 15. Aldosterone antagonist Aldosterone : Na & water retension (a) Expansion of e.c.f. volume → increased cardiac preload (b) Fibroblast proliferation and fibrotic change in myocardium → worsening systolic dysfunction and pathological remodeling.
- 16. Contd. (c) Hypokalemia and hypomagnesemia → increased risk of ventricular arrhythmias and sudden cardiac death. d) Enhancement of cardiotoxic and remodeling effect of sympathetic overactivity
- 17. Contd. • Drugs: spironolactone , eplerenone • Indicated as add-on therapy to ACE inhibitors + other drugs in moderate-to-severe CHF • Retard disease progression, reduce episodes of decompensation and death • Low doses (12.5–25 mg/day) of spironolactone to avoid hyperkalaemia • Help restoration of diuretic response to furosemide when refractoriness has developed
- 18. DIURETICS Loop diuretics (Furosemide,bumetedine) ↓preload ↓edema & pulmonary congestion Used when there is fluid overload Thiazides – used with loop diuretics (when Patient refractory to to loop diuretics alone )
- 19. Relief of symptoms and restoration of cardiac performance Vasodilators combination Isosorbide dinitrate + Hydralazine(arteriolar dilator) (Venodilator) ↓ preload ↓ afterload Monotherapy – problematic Isosorbide dinitrate - tolerance Hydralazine - tachycardia + fluid retention ↓ mortality
- 20. Pre- and after load reduction • Sodium nitropruside • high efficacy i.v. dilator • Action is very fast and brief
- 21. Cardiac Glycosides = Digitalis compounds DIGOXIN Positive Inotropic effect •increase the myocardial contractility and improves cardiac output without proportionate increase in Oxygen consumption
- 24. Cardiac glycoside Digoxin Acts by blockade of Na+K+ATPase pump in phosphorylated state – action is slow (Hyperkalemia cause dephosphorylation of the ATPase --- reducing the drug's binding and effect) Positive inotropic effect - CO↑ ↓HR – due increased vagal tone AV conduction ↓ PR interval prolongation Given orally Once a day Renal excretion Large Vd – 6-8L/kg T1/2 – 36-48hrs
- 25. Cardiac glycoside = Digoxin ADR Cardiac Bradycardia –Rx by atropine Tachyarrhythmias – KCl IV/oral For supraventricular arrhythmias Propranolol Ventricular tachycardia – lignocaine Severe toxicity can be Rx by Digitalis Immune Fab – neutralizing effect Digoxin can cause all almost every type of arrhythmia Extracardiac Nausea vomiting Headache dizziness Psychoses Visual disturbances Gynecomastia
- 26. Current status of Digoxin in HF Other use • Atrial Fibrillation (atrial rate -500/min) to control ventricular rate – by ↓AV conduction and ↑ERP of AV node • Atrial flutter – atrial rate is 200–350/ min – convert AFl to AF does not reduce mortality Patients who remain symptomatic despite maximal therapy with ACE inhibitors and beta blockers
- 27. Contd. • Paroxysmal supraventricular tachycardia – common arrhythmia with a rate 150–200/min and 1 : 1 A-V conduction – i.v. digitalis increases vagal tone and depresses the path through the SA/A-V node, or the ectopic focus, and terminates the arrhythmia – Adenosine and verapamil are more effective, less toxic and act faster – Digitalis:reserved for preventing recurrences
- 28. Contraindications • Hypokalemia • Elderly, renal or severe hepatic disease • Myocardial ischaemia: • Thyrotoxicosis • Myxoedema • Ventricular tachycardia • Partial A-V block • Wolff-Parkinson-White syndrome
- 29. Inotropic agents Dopamine •Low dose infusion :2- 5 μg/kg/min D1 action –renal vasodilation ↑ renal blood flow + Na+ excretion • Intermediate dose infusion 5-10μg/kg/min – is used in Rx β1 action – inotropic effect • High dose infusion - >10 μg/kg/min α action - vasoconstriction Dobutamine β1 agonist – prominent inotropic effect IV infusion No effect on Dopamine receptor
- 30. Inotropic agents Inodilators = PDE III inhibitors = Milrinone Amrinone Mechanism: •↑ level of intracellular cAMP • Positive inotropic + vasodilator effect ADR •Amrinone – thrombocytopenia • less with Milrinone Short term IV infusion
- 31. Levosimendan • calcium sensitizer –increases the sensitivity of the heart to calcium + Vasodilator effect • opens ATP-sensitive K+ channel in vascular smooth muscle cells to cause vasodilatation • Inodilator • infused i.v. short term
- 32. Nesiritide Recombinant Brain Natriuretic Peptide (BNP) Vasodilation + salt & water excretion↑ Sacubitril+valsatran combination •orally active neprilysin in inhibitor •Prevents the degradation of endogenous ANP, BNP and other vasodilator peptides •Actions:Vasodilatation,natriuresis,diuresis •Combined with valsartran:prevents death &decompensation
- 33. Tolvaptan • V2 receptor antagonist •Uses:SIADH &advanced CHF •Short term improvement by increasing water excretion •No long term benefit
- 34. Digoxin is not indicated in (a) Atrial flutter (b) Atrial fibrillation (c) High output failure (d) PSVT
- 35. 19) Drugs that reduce myocardial remodelling in CHF include all of the following except: (a) Carvedilol (b) Digoxin (c) Enalapril (d) Spironolactone
- 36. • All are true about starting of beta-blocker therapy in a patient with congestive heart failure except: (a) They should be started with optimum doses (b) They should be gradually increased over weeks (c) Special precautions should be taken in cases of NYHA class III and IV (d) Carvedilol and metoprolol are the preferred drugs
- 37. • All of the following drugs are used for the treatment of congestive heart failure except: • (a) Nitroglycerine • (b) Spironolactone • (c) Nesiritide • (d) Trimetazidine
- 38. • Which of the following is a venodilator? • (a) Hydralazine • (b) Minoxidil • (c) Nitroprusside • (d) Nifedipine
- 39. • Which of the following drugs can prolong survival in patients with CHF? • (a) Furosemide • (b) Inamrinone • (c) Losartan • (d) Digoxin
- 40. • Which of the following drugs can prolong survival in patients with CHF? • (a) Furosemide • (b) Inamrinone • (c) Losartan • (d) Digoxin
- 41. • Drugs associated with clinically useful or physiologically important positive inotropic effects include all of the following except: • (a) Amrinone • (b) Enalapril • (c) Digoxin • (d) Dobutamine
- 42. • Which of the following drugs is beneficial in a refractory congestive heart failure by increasing cardiac contractility and decreasing preload and afterload? • (a) Amiloride • (b) Amiodarone • (c) Amrinone • (d) Carvedilol
Notes de l'éditeur
- In addition to maintaining normal cardiovascular homeostasis, the hormones and neurohormonal systems described in the last few slides also play an important role in compensating for the diminished cardiac output seen in patients with early heart failure. But it is also known that over time, these same neurohormone systems eventually become detrimental and contribute to the progression of heart failure. Why does this happen? Physiologists now recognize that the neurohormonal mechanisms activated in heart failure are identical to those normally triggered when cardiac output and blood pressure are threatened (e.g., intense physical exercise, hemorrhage), but with an important difference. Under normal circumstances, the release of neurohormones is generally successful in reversing the hemodynamic abnormalities seen in acute low volume/low output states, and consequently, neurohormonal activity eventually subsides. In contrast, neurohormonal activation never “turns off” in the setting of heart failure; rather, is always “on” in an attempt to compensate for the failing heart’s chronic inability to maintain normal cardiovascular homeostasis. Furthermore, the chronic presence of circulating neurohormones tends to exacerbate the hemodynamic abnormalities in heart failure, which only encourages further remodeling and neurohormone release and, thus, further hemodynamic deterioration. Thus, a vicious cycle develops whose end result is progressive ventricular dysfunction and death.
- Cardiac performance is a function of four primary factors Preload Afterload Contractility Heart rate
- Safety margin is low
- Levosimendan calcium sensitizer – it increases the sensitivity of the heart to calcium + Vasodilator effect