Anti anginal drugs & heart failure drugs

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Anti anginal drugs & heart failure drugs

  1. 1. Anti Anginal Drugs & Heart Failure Josephus P. Sibal, MD !1
  2. 2. Objectives• Explain the pathophysiology of angina and congestive heart failure• Discuss the kinetics, pharmacologic actions, dosage, and interactions of – Anti anginal drugs – Heart failure drugs !2
  3. 3. !3
  4. 4. !4
  5. 5. Types of Heart Failure:Left-sided HF vs Right-sided HF Systolic HF vs Diastolic HF (Heart failure with low EF vs Heart failure with preserved EF) Acute HF vs Chronic heart failureLow-output HF vs High-output HF !5
  6. 6. Etiologies of Left-sided and Right-sided Heart Failure Left-sided Heart Failure Right-sided FailureLV end diastolic Left-sided heart failure pressure (MI, CAD, dilated cardiomyopathy, RV systolic overload valvular heart disease, AI, (cor pulmonale, 1° PHPN, AS, hypertension) congenital HD with shunt anomaly)↑ LA pressure (MS) ↑ RA pressure (TS, TR)Fluid overload (renal failure, iatrogenic) !6
  7. 7. Differentiation of Systolic and DiastolicHeart FailureParameters Systolic DiastolicI. History: CAD ++++ + DM +++ + Valvular Heart Dse ++++ -II. Physical Examination: HPN ++ ++++ Jugular distention +++ + Cardiomegaly +++ + Soft Heart Sounds ++++ + S3 Gallop +++ + S4 Gallop + +++ Edema !7 +++ +
  8. 8. Differentiation of Systolic and DiastolicHeart FailureParameters Systolic DiastolicIII. Chest X-ray: Cardiomegaly +++ + Pulm. Congestion +++ +++IV. ECG: LVH ++ ++++ Q Waves ++ +V. Echocardiogram: Low ejection fraction ++++ - LV Dilatation ++ - LVH ++ ++++ !8
  9. 9. Pump failure = low CO !9
  10. 10. CO = SV x HR !10
  11. 11. Stroke Volume Preload Contractility Afterload !11
  12. 12. Preload!12
  13. 13. Afterload !13
  14. 14. BP = SV x TPR !14
  15. 15. Contractility + Preload + Afterload Heart Rate x Stroke VolumeCardiac Output x Total Peripheral Resistance Blood Pressure !15
  16. 16. Compensatory Mechanisms • Cardiac • Neurohumoral !16
  17. 17. Boyle’s Law !17
  18. 18. Frank Starling !18
  19. 19. LAPLACE LAW Pressure x Radius Wall Stress = 2 (Wall Thickness) !19
  20. 20. Model of Wall Stress !20
  21. 21. !21
  22. 22. !22
  23. 23. !23
  24. 24. tar ling Ventricular end- k-S Fra n diastolic volumeSV La Pla c e Ventricular mass !24
  25. 25. Decreased BP Sympa NS R-A system ADHContractility HR Vasoconstriction Circulating vol Arteriolar Venous Maintain BP Venous return to heart ( preload) C.O. (+) (+) S.V. !25
  26. 26. Heart Failure 
 
Failure of compensatory mechanisms !26
  27. 27. Cardiac Output Left Ventricular End-Diastolic Volume !27
  28. 28. Left Ventricular End-Diastolic Pressure hypertrophy!28 Left Ventricular End-Diastolic Volume
  29. 29. g rlin nk - St a Ventricular a Fr end-diastolicSV volume Atrial La Pressur CHF Pl e ac e Ventricular mass !29
  30. 30. Decreased BP Sympa NS R-A system ADHContractility HR Vasoconstriction Circulating vol Arteriolar Venous Maintain BP Venous return to heart ( preload) (+) C.O. (-) Pulmonary (+) congestion S.V. !30
  31. 31. NYHA Classification of CHF:Functional Description General Guide Class I Dyspnea occurs with Climbs ≥ 2 flights of greater than ordinary stairs with ease physical activity. II Dyspnea occurs with Can climb 2 flights of ordinary physical stairs but with difficulty activity. III Dyspnea occurs with Can climb ≤ 1 flight of less than ordinary stairs physical activity. IV Dyspnea may be Dyspnea at rest present even at rest. !31
  32. 32. Signs and symptoms of Left-sided and Right-sided Heart Failure:Symptoms of Left HF:Easy fatigability Exertional dyspneaConfusion OrthopneaPND Cough Signs of Left HF:Tachypnea TachycardiaRales S3/4 Gallop Wheezes !32
  33. 33. Signs and symptoms of Left-sided and Right-sided Heart Failure:Symptoms of Right HF:Easy fatigability Early satiety RUQ discomfortSigns of Right HF:Elevated JVPHepatomegalyAscitesLower extremity edema !33
  34. 34. !34
  35. 35. !35
  36. 36. Diagnostic Tests:1. Chest X-ray2. ECG3. 2-D Echo !36
  37. 37. What to do? !37
  38. 38. !38
  39. 39. !39
  40. 40. !40
  41. 41.   Cardiac Drugs for HF, Classified According to Hemodynamic I Effects. Mainly Preload Contractility Mainly Afterload Unloaders Unloaders (Venous Dilators) (Arterial Dilators)Diuretics Digoxin Ace-inhibitorsNitrates Dobutamine Angiotensin-II Dopamine Antagonists Hydralazine Nitroprusside !41
  42. 42. • Vasodilators • Inotropic• Afterload agents Congestiveunloader Heart Failure• Preloadunloader ↑ Systemic vascular ↓ Cardiac output resistance (afterload) ↑ LV end diastolic ↑ Blood volume pressure (preload) Compensatory• ACE inhibitors Responses• ß blockers ↑ Renin-angiotensin aldosterone system• Diuretics ↑ Sympathetic tone ↑ ADH2release !4
  43. 43. 2. Treat all precipitating causes of CHF.Cardiac causes:• Non-compliance with medicines• Arrhythmia• Ischemia or infarction• Uncontrolled hypertension• RHD, myocarditis, valvular dse, MR• EndocarditisNon-cardiac causes:• Renal Failure (fluid overload)• Anemia• Pulmonary embolism• Infection• Delivery after pregnancy• Lifestyle !43
  44. 44. 3. Assess which of the following contributes to a decrease in cardiac output and must be corrected: a. Increase in afterload b. Increase in preload c. Decrease in contractility d. Increase in heart rate !44
  45. 45. 4. If poor response to medical treatment: a. Maximize medical treatment. b. Consider a surgical option !45
  46. 46. Diseases causing High Output HF:• Anemia• Febrile disorders• Pregnancy• Beri-beri• Renal shunts• Arteriovenous fistulas• Thyrotoxicosis !46
  47. 47. Usual Progression of Symptoms in Left-sided HF• Dyspnea upon exertion• PND – Cardiac type: occurs 2-4 hrs after sleep – Pulmonary type: variable onset• Orthopnea – Cardiac type: occurs after 5 mins – Pulmonary type: immediate onset• Dyspnea at rest• Lower extremity edema !47
  48. 48. Clinical Manifestations Based on Severity of Heart Failure:• Early CHF (NYHA Class I): – May be asymptomatic• Mild to Moderate CHF (NYHA Class II-III): – Mild, non-specific symptoms – PE may be normal• Severe CHF (NYHA Class IV): – Signs and symptoms are obvious – Patients in marked distress: (orthopneic with distended neck veins) !48
  49. 49. Usual Cause of Death in Patients with CHF: 
• Fatal ventricular arrhythmia (sudden cardiac death)• Refractory heart failure • Pulmonary embolism !49
  50. 50. Precipitating Causes of Acute HFCardiac causes:• Non-compliance with medicines• Arrhythmia• Ischemia or infarction (superimposed)• Uncontrolled hypertension• RHD, myocarditis, valvular dse, MR• Endocarditis !50
  51. 51. Treatment Options in Acute HF: • Removal of precipitating cause • Morphine sulphate IV • Oxygen • Potent diuretics IV • Rapid digitalization • Rapid preload and afterload reduction • Intravenous titratable inotropic therapy • Rotating tourniquets • Intra-aortic counterpulsation • Cardiac surgery !51
  52. 52. Precipitating Causes of Acute HFNon-cardiac causes:• Renal Failure (fluid overload)• Anemia• Pulmonary embolism• Infection• Delivery after pregnancy• Lifestyle (stress) !52
  53. 53. Basic Pharmacology of Drugs used in Heart Failure• Digitalis – Purple foxglove (Digitalis purpurea) – Digoxin is the prototype – 65-80% absorbed after oral administration – Widely distributed in tissues – 2/3 is excreted unexchanged in the kidneys – Half life is 36-40 hours !53
  54. 54. Digitalis• Inhibits Na+, K+, ATPase pump, or the sodium pump• Increases contraction of the sarcomere by increasing free calcium concentration• Done by: increase of intracellular sodium via Na+, K+, ATPase inhibition, second, relative reduction in calcium expulsion !54
  55. 55. Digitalis• Net effect is a distinctive increase in cardiac contractility• Useful in dilated cardiomyopathy• Given at a slow loading dose of 0.125 -0.25 mg per day or rapid loading of 0.5 mg-0.75 mg q 8 hours for three doses• Digoxin has no net effect on mortality but reduces hospitalization !55
  56. 56. Effects of Digoxin of other Cardiac Tissues !56
  57. 57. Effects in other organs• Since cardiac glycosides affect all excitable tissues, smooth muscle and CNS effects are notable. – Nausea, vomiting, diarrhea, anorexia – Disorientation, hallucinations, visual disturbances !57
  58. 58. Interactions with K+, Ca++, Mg++• Potassium and digitalis inhibit each other’s binding to Na+, K+, ATPase; therefore hyperkalemia reduces the enzyme binding of cardiac glycosides, where are hypokalemia reduces its actions. • Hyperkalemia can precipitate bradycardia and hypokalemia can limit the effects of digitalis !58
  59. 59. Interactions with K+, Ca++, Mg++• Ca facilitates the effects of digitalis by overloading of intracellular calcium stores. • Digitalis-induced abnormal automaticity !59
  60. 60. Positive Inotropics• Bipyridines – Milrinone is a phosphodiestarase isoenzyme 3 inhibitor (PDE 3 inhibitor) – Increase myocardial contractility by increasing calcium influx in the cardiac muscle during the action potential. – Compared to inamrinone, milrinone is less likely to cause arrhythmias and can be used in acute heart failure or severe exacerbation of chronic heart failure. !60
  61. 61. Positive Inotropics• Beta adrenoceptor stimulants – Dobutamine – Selective B1 agonist – Increases cardiac output by decreasing ventricular filling pressure – Produce angina or arrhythmia – Given in mcg/kg BW – Maximum dose is 20 mcg/kg BW !61
  62. 62. Positive Inotropics• Dopamine – May also be used in acute heart failure where there is a need to increase the BP – It stimulates dopaminergic, beta, alpha effects at different doses – Given in mcg/kg BW, max 20 mcg/Kg BW !62
  63. 63. Drugs Without Positive Inotropic Effects• Diuretics• ACE inhibitors• ARBs• Aldosterone antagonist• Beta blockers• Vasodilators !63
  64. 64. Diuretics• Prototype: Furosemide• Mainstay of heart failure• No direct effect on cardiac contractility• Major action is to reduce venous pressure and ventricular preload• Reduction in salt and water retention• Concomitant hypokalemia may develop • Usual dose: 40 mg IV or PO dose, increased until signs of heart failure improve !64
  65. 65. Diuretics• Thiazide type diuretics – Hydrochlorothiazide – May result to hyponatremia secondary to potassium excretion – Usual dose 12.5 mg to 25 mg OD, in combination with ARBs or ACEi• K+ sparing diuretics – Spironolactone or eplerenone – Aldosterone antagonist – Usual dose: 25-50 mg OD PO !65
  66. 66. ACE Inhibitors• Blockade of RAAs• Given to patients with LV dysfunction• Reduction of preload (reduce salt & water retention) and afterload (reduce peripheral resistance)• Slow the progression of ventricular dilatation• Decrease long term remodeling of the heart and vessels !66
  67. 67. ACE Inhibitors• Prototype: captopril• Most commonly used: enalapril• Patient may benefit from asymptomatic to severe heart failure• Usual dose: captopril 25 mg q 6, enalapril 10 mg OD, !67
  68. 68. Angiotensin Receptor Blockers• Produce similar benefits as ACEi• Given to patients who are incessant to cough.• Prototype: losartan• Usual dose: losartan 50 mg OD, eposartan 600 mg OD, candesartan 8 mg OD, irbesartan 150 mg OD, telmisartan 40 mg OD, olmesartan 20 mg OD !68
  69. 69. Vasodilators• Nesiritide• Endogenous peptide (brain natriuretic peptide) or BNP• Increases cGMP in smooth muscle cells and reduces venous & arteriolar tone• Causes diuresis• Preload reducing agent !69
  70. 70. Beta Blockers• Bisoprolol, carvedilol & metoprolol• Attenuate the high concentrations of circulating cathecolamines• Decreasing heart rate, decrease remodeling by reduction of the mitogenic activity of cathecolamines !70
  71. 71. !71
  72. 72. !72
  73. 73. Antianginal drugs !73
  74. 74. Pathophysiology of Angina !74
  75. 75. !75
  76. 76. Determinants of Coronary Blood Flow & Myocardial Oxygen Supply• Coronary blood flow is directly related to: – perfusion pressure (aortic diastolic pressure) – Duration of diastole (vs tachycardia)• Coronary blood flow is inversely proportional to the coronary vascular bed resistance !76
  77. 77. Determinants of Vascular Tone• Increasing cGMP (dephosphorylation of myosin light chains) – Nitric oxide• Decreasing intracellular Ca2+ (calcium channel blockers which cause vasodilatation, decrease heart rate)• Stabilizing or preventing depolarization of vascular smooth muscle cell membrane (increase the permeability of K+ channels• Increasing cAMP (inactivation of myosin light chain kinase which causes vasodilatation) this mechanism is caused by beta blockers. !77
  78. 78. • Vasodilate• Reduce rate !78
  79. 79. Nitrates & Nitrites• Nitroglycerin – Prototype – Causes activation of guanylyl cyclase and an increase in cGMP, the first step in smooth muscle relaxation – Oral bioavailability is low – Sublingual dose eliminated first pass effect !79
  80. 80. Nitrates• No effect on skeletal muscles• Direct effect of NTG is increased venous capacitance and decreased ventricular preload• Decreases platelet aggregation• Oral controlled release tablets, sublingual tablets, buccal spray, transdermal patch & IV• Must NOT be taken with ED meds !80
  81. 81. Nitrates• IV may be started at 0.5 mg/hr up to 5 mg/ hr• Oral preparations can be given 30 mg to 60 mg OD !81
  82. 82. !82
  83. 83. Calcium Channel Blockers• L-type calcium channel blocker• Dihydropyridines vs non dihydrophyridines• Reduces the frequency of opening in smooth muscle content this gives decreased transmembrane content• Decreased heart rate via dec sinus node pacemaker rate !83
  84. 84. Calcium Channel Blockers• Tachyarrhythmias – Diltiazem & verapamil HPN Amlodipine & nifedipine !84
  85. 85. Beta blockers• Effects are due to dec HR, dec BP, dec contractility• Effect would be decreased oxygen demand at rest and exercise• Longer diastolic perfusion time !85
  86. 86. Beta blockers• Contraindicated with: – Asthma – Severe bradycardia, AV dysfunction – Severe LV dysfunction – CHF NYHA IV !86
  87. 87. Partial Fatty acid Oxidation (pFOX)• Trimetazidine• metabolic mediators, inhibit the fatty oxidation pathway in the myocardium !87
  88. 88. Ivabradine• Activation of the If channel or the funny bone channel• Decreases the heart rate without the effect of hypotension !88
  89. 89. Other Drugs• Sulfonylureas• thiazolidinediones !89

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