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2.CHF.pptx Health .........................
- 1. Congestive Heart failure PharmacologyII Dr. Mohamed Ibrahim
- 2. Complex and progressivedisorder Heart is unable to pump sufficient blood to meet body needs Impaired ability to adequately FILL with (Diastolic HF) &/or EJECT blood (Systolic HF)
- 3. Etiology: Very high workloadsplaced on the heart Atherosclerotic heart disease Myocyte loss or decreased myocyte contractility Ischemic heart disease (myocardial infarction) Congenital heart disease Preload & Afterload Weak heart = ↆ CO
- 4. Increase of venousreturn causes increase of stretch of myocardium = Increased force to pump blood out.
- 5. Ejection Fraction: Definition: Itis the ratio of SV compared to EDV. SV 70 = EDV 135 Importance: It is used as indicator for myocardial contractility. Normal value: about 50 – 60 %. X 100 X 100 =
- 6. Heart is unableto pump sufficient blood to meet body needs = Impaired ability to EJECT blood CONGESTION or OEDEMA (Increase in ExtraCellular Fluid Volume=Blood & Interstitial fluid) In Right HF: Peripheral Oedema occurs In Left HF: Pulmonary Congestion occurs (leads to Dyspnea)
- 8. 8 Signs & Symptomsof Right-sided HF Jagular vein distension Peripheral edema
- 11. Patients complain of: Dyspnoea(sensation of breathlessness) on exertion Orthopnoea (breathlessness when lying down) Nocturnal Dyspnoea Tachycardia, sweating,cold extremities Peripheral edema cardiomegaly Fatigue and exercise intolerance
- 13. • Carry bloodtoward the heart. • Muscles surround the veins so that when the muscles contract, the veins squeeze and the blood is pushed along the vessels against gravity. just as squeezing a toothpaste tube ejects toothpaste. • Have valves to prevent backflow of blood • Venous blood flow is under low pressure (Venous return / Preload) (Afferent vessels)
- 14. Myocardial Hypertrophy INITIALLY, stretchingof heart muscle leads to STRONGER CONTRACTION BUT EXCESSIVE ELONGATION results in WEAKER contractions (Systolic HF)
- 15. Cardiac Remodeling (Hypertrophy) If theheart is unable to pump this extra volume,the venous pressure will increase leading to Oedema Activation of RAAS
- 16. Goals of Pharmacological Interventions AcuteHeart Failure: 1. ↑↑↑ CO by ↑↑ Contractility → +ve Inotropics. 2. Relief of edema and congestion → Diuretics. Chronic Heart Failure: 1. ↆↆ Workload of the heart by: ↆↆ Afterload (arteriodialtors) & ↆↆ Preload (venodilators) 2. Relief of edema and congestion by: Diuretics. 3. To reverse cardiac remodeling: ACE inhibitors, β-blockers
- 17. Goals of Pharmacological Interventions Inorder to achieve this, one or more of 6 classes are used: Diuretics Direct Vasodilators Inotropic Agents ARBs β- Blockers ACEIs
- 18. (1) + veinotropics
- 19. Inotropic Agents • Positiveinotropic agents enhance cardiac contractility and,thus, increase Cardiac Output (C.O.) • Although these drugs act by different mechanisms, the inotropic action is the result of an increased cytoplasmic CALCIUM concentration that enhances the contractility of cardiac muscle.
- 20.
- 22. Mechanism of action: bindsto the K+ binding site in the Na+/K+ ATPase pump partial inhibition of the pump ↆↆ Na+ efflux ↑↑ intracellular Na+ ↆↆ Na+/ Ca2 exchange ↆↆ Ca2+ efflux ↑↑ intracellular Ca2+ +ve inotropic ↑↑CO 1. Mechanical effect ( force of contraction) Digoxin
- 23. K+ relation totherapeutic efficacy of cardiac glycosides: K+ competes with Digitalis for its binding site to Na+/K+ ATPase pump. If K+ levels are low digoxin will work unopposed therapeutic effect of digoxin and may reach toxicity so hypokalemia digitalis toxicity. If k+ levels are high k+ will displace digoxin from its binding site therapeutic effect of digoxin so hyperkalemia digitalis activity. So it is essential to keep k+ level in normal physiologic level Hypokalemia may be induced by K-depleting diuretics (e.g. Loop, Thiazide) which are used to treat edema. For prevention of hypokalemia either k+-supplement or k+-sparing diuretics.
- 24. • Vagal toneis also enhanced, so both heart rate and myocardial oxygen demand decrease. • Digoxin slows conduction velocity through the AV node • Low-dose of digoxin → ↆↆↆ sympathetic activation with minimal effects on contractility. i.e. ↆↆ effect of A & NA on heart → ↆↆ HR (Bradycardia) 2. Electrical effect
- 25. • Kidney: Ithas weak diuretic effect why? Digitalis → ↑↑ C.O. → ↑↑ Renal perfusion → ↆↆ Renin → ↆↆ Aldosterone → ↑↑ Na+/H2O loss in urine (diuresis) → Partial improvement of congestion & edema. • CNS: overdose → hallucinations, blurred vision • Hormones: gynecomastia due to estrogenic activity
- 26. Management of Digoxintoxicity Stop administration of digitalis & K-depleting diuretics. Monitoring of K+, and give KCl (K-competes with digioxin on Na/K – ATPase). Antiarrhythmic drugs to control ventricular arrhythmia. Atropine to control the bradycardia and AV block. Specific digoxin antidote (Digibind).
- 27.
- 28. • Dobutamine anddopamine, improve cardiac performance by causing positive inotropic effects. Both drugs must be given by intravenous infusion and are primarily used in the short-term treatment of acute HF in the hospital setting. β - agonist Dopamine, Dobutamine
- 29. Dopamine Dobutamine β1 inheart contractility & HR. D1 in kidney dilate renal blood vessel RBF urine output. CO & relief edema Selectively Stimulate β1 in heart contractility. advantage: contractility with minimal increase in HR. IV infusion for short term control of severe acute HF patients in hospitals Why do β-Adrenergic agonists possess inotropic effects? Gs protein coupled receptor : Adenylcyclase cAMP Ca2+ inc. ATP
- 30.
- 31. ATP Adenylcyclase cAMPPhosphodiesterase-3 Inactive Ca2+ inc. • Milrinone is a phosphodiesterase-3 inhibitor that increases the intracellular concentration of cAMP. • Like β-adrenergic agonists, this results in an increase of intracellular calcium and, therefore, cardiac contractility. cAMP : Myocardial contractility C.O. IV infusion for short control of acute HF in hospitalized patients PDEIs Milrinone
- 32.
- 33. 1. Block theenzyme that converts angiotensin I to angiotensin II. 2.Diminish the inactivation of bradykinin. 3.Vasodilation occurs as a result of decreased levels of the vasoconstrictor angiotensin II and increased levels of bradykinin (a potent vasodilator). 4. ↆ Aldosterone secretion Na/H2O retention relief edema 5. Reversal of cardiac and vascular smooth muscle remodeling. Actions on the heart: Vascular resistance (afterload) Venous tone (preload) Cardiac output 2- ACEIs - pril
- 34.
- 35. Cardiac Remodeling (Hypertrophy) ACEIs AT1 ACE inhibitorsare known to increase tissue bradykinin accumulation. Bradykinin has antigrowth effects and reduces vasomotor tone. Increased kinin activation resulting from ACE inhibition may attenuate structural remodeling in the cardica muscles.
- 36.
- 37. Depending on theseverity of HF,ACE inhibitors may be used in combination with: Diuretics, β-blockers, Digoxin, Aldosterone antagonists, Hydralazine / Isosorbide
- 38. Adverse effects: Posturalhypotension (due to vasodilation). Renal dysfunction Hyperkalemia (due to ↆↆ aldosterone). Monitor K+ level Persistent dry cough Angioedema (rare) Teratogenicity ( in pregnant women)
- 39.
- 40. Valsartan & Losartan •Competitive antagonists of the angiotensin II type 1 receptor (AT1R). • DO NOT affect bradykinin levels. • Substitute for ACE inhibitors in those patients who cannot tolerate the latter (severe cough or angioedema, which are thought to be mediated by elevated bradykinin levels) • Have the same action of ACE inhibitors on preload and afterload. 3- ARBs - sartan
- 41. Adverse effects: Similar tothat of ACE inhibitors. However, ARBs have a lower incidence of cough and angioedema. Like ACE inhibitors, ARBs are in pregnancy.
- 42.
- 43. Vasodilators • Dilation ofvenous blood vessels decrease in cardiac preload by increasing venous capacitance (Isosorbide dinitrate) • Dilation of arterial blood vessels reduce systemic arteriolar resistance and decrease afterload (Hydralazine) • If the patient is intolerant to ACE inhibitors, or if additional vasodilator response is required, a combination of vasodilator may be used.
- 44. Vasodilators Arterio-dilator Veno-dilator Hydralazine Isosorbiddinitrate ↆ PR → ↆ Afterload → ↑ CO → ↑ renal bld. flow →↑ GFR → relief of edema ↆ PR → ↆ Preload → ↆ ↆ Venous return → ↆ ↆ Venous pressure → ↆ ↆ edema
- 45.
- 47. • Diuretics relievepulmonary congestion and peripheral edema. • Naturesis & diuresis blood volume venous return Preload • Blood volume venous pressure venous congestion Edema • This decreases cardiac workload and oxygen demand. • Diuretics may also decrease afterload by reducing plasma volume, thereby decreasing blood pressure. • Loop diuretics are the most commonly used diuretics in HF. Thiazides, Loop diureteics, K+ sparing diuretics 5- Diuretics
- 48. Hydrochlorothiazide Used for longterm therapy of HF when edema is not too great. Efficiency of Thiazide diuretics is dependent on kidney function i.e. ineffective when glomerular filteration rate (GFR) is low. Furosemide They produce profound diuresis even if GFR is low (used in renal failure patients) Drugs of choice for patients with severe heart failure. Spironolactone Very weak diuretics In CHF adjuvant therapy to counteract hypokalemia Diuretics Thiazides Loop diuretics K+ sparing
- 49. Aldosterone antagonists Adverse effects: Nonselective aldosterone antagonist i.e. binds to androgen and progesterone receptors • Gynecomastia (due to blocking of testosterone receptors) • Hyperkalemia (K+ level should be monitored in case • of combination with ACE inihibitors & AgII antagonists).
- 50. (6) β -Blockers
- 51. Block β1 inthe heart & kidney → ↆↆ HR & Renin Protecting heart excessive sympathetic stimulation HF progression Carvedilol 1 Antioxidant activity. 2 Blocks α1 in the Blood vessels → V.D. → ↆↆ Preload & Afterload Metoprolol, Bisoprolol, Carvidilol 6- β blockers
- 52. • β-blockade isrecommended for all patients with chronic, stable HF. • SHOULD NOT be used to initiate therapy of acute heart failure (C.I. in acute heart failure) as they may worsen case by –ve inotropic effect. • Precautions: Excessive beta-blockade contractility so doses must be very low initially and then gradually increased.
- 53.