This document discusses anti-anginal drugs and heart failure. It begins by explaining the pathophysiology of angina and congestive heart failure. It then discusses different types of heart failure and the etiologies of left-sided and right-sided heart failure. The document outlines the pharmacology of various drugs used to treat heart failure, including diuretics, ACE inhibitors, beta-blockers, and vasodilators. It concludes by discussing treatment options for acute heart failure.

1. Anti Anginal Drugs & Heart Failure
Josephus P. Sibal, MD
!1

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

4. !4

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 failure
Low-output HF vs High-output HF
!5

6. Etiologies of Left-sided and
Right-sided Heart Failure
Left-sided Heart Failure Right-sided Failure
LV 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. Differentiation of Systolic and Diastolic
Heart Failure
Parameters
Systolic
Diastolic
I. History:
CAD
++++
+
DM
+++
+
Valvular Heart Dse
++++
-
II. Physical Examination:
HPN
++
++++
Jugular distention
+++
+
Cardiomegaly
+++
+
Soft Heart Sounds
++++
+
S3 Gallop
+++
+
S4 Gallop
+
+++
Edema
!7
+++
+

8. Differentiation of Systolic and Diastolic
Heart Failure
Parameters
Systolic
Diastolic
III. Chest X-ray:
Cardiomegaly
+++
+
Pulm. Congestion
+++
+++
IV. ECG:
LVH
++
++++
Q Waves
++
+
V. Echocardiogram:
Low ejection fraction
++++
-
LV Dilatation
++
-
LVH
++
++++
!8

9. Pump failure = low CO
!9

10. CO = SV x HR
!10

11. Stroke Volume
Preload
Contractility
Afterload
!11

12. Preload
!12

13. Afterload
!13

14. BP = SV x TPR
!14

15. Contractility + Preload + Afterload
Heart Rate x Stroke Volume
Cardiac Output x Total Peripheral Resistance
Blood Pressure
!15

16. Compensatory Mechanisms
• Cardiac
• Neurohumoral
!16

17. Boyle’s Law
!17

18. Frank Starling
!18

19. LAPLACE LAW Pressure x Radius
Wall Stress = 2 (Wall Thickness)
!19

20. Model of Wall Stress
!20

21. !21

22. !22

23. !23

24. tar
ling Ventricular end-
k-S
Fra
n
diastolic volume
SV
La
Pla
c e
Ventricular mass
!24

25. Decreased BP
Sympa NS
R-A system
ADH
Contractility
HR
Vasoconstriction
Circulating vol
Arteriolar Venous
Maintain
BP Venous return to
heart ( preload)
C.O.
(+)
(+)
S.V. !25

26. Heart Failure
Failure of compensatory mechanisms
!26

27. Cardiac Output
Left Ventricular End-Diastolic Volume
!27

28. Left Ventricular End-Diastolic Pressure
hypertrophy
!28
Left Ventricular End-Diastolic Volume

29. g
rlin
nk
- St
a
Ventricular
a
Fr
end-diastolic
SV volume Atrial
La
Pressur CHF
Pl e
ac
e Ventricular
mass
!29

30. Decreased BP
Sympa NS
R-A system
ADH
Contractility
HR
Vasoconstriction
Circulating vol
Arteriolar Venous
Maintain
BP Venous return to
heart ( preload)
(+)
C.O. (-) Pulmonary
(+) congestion
S.V. !30

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. Signs and symptoms of Left-sided and
Right-sided Heart Failure:
Symptoms of Left HF:
Easy fatigability
Exertional dyspnea
Confusion
Orthopnea
PND
Cough
Signs of Left HF:
Tachypnea
Tachycardia
Rales
S3/4 Gallop
Wheezes
!32

33. Signs and symptoms of Left-sided and
Right-sided Heart Failure:
Symptoms of Right HF:
Easy fatigability
Early satiety
RUQ discomfort
Signs of Right HF:
Elevated JVP
Hepatomegaly
Ascites
Lower extremity edema
!33

34. !34

35. !35

36. Diagnostic Tests:
1. Chest X-ray
2. ECG
3. 2-D Echo
!36

37. What to do?
!37

38. !38

39. !39

40. !40

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-inhibitors
Nitrates Dobutamine
Angiotensin-II
Dopamine Antagonists
Hydralazine
Nitroprusside
!41

42. • Vasodilators
• Inotropic
• Afterload agents
Congestive
unloader
Heart Failure
• Preload
unloader
↑ 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. 2. Treat all precipitating causes of CHF.
Cardiac causes:
• Non-compliance with medicines
• Arrhythmia
• Ischemia or infarction
• Uncontrolled hypertension
• RHD, myocarditis, valvular dse, MR
• Endocarditis
Non-cardiac causes:
• Renal Failure (fluid overload)
• Anemia
• Pulmonary embolism
• Infection
• Delivery after pregnancy
• Lifestyle
!43

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. 4. If poor response to medical
treatment:
a. Maximize medical treatment.
b. Consider a surgical option
!45

46. Diseases causing High Output HF:
• Anemia
• Febrile disorders
• Pregnancy
• Beri-beri
• Renal shunts
• Arteriovenous fistulas
• Thyrotoxicosis
!46

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. 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. Usual Cause of Death in Patients with CHF:
• Fatal ventricular arrhythmia
(sudden cardiac death)
• Refractory heart failure
• Pulmonary embolism
!49

50. Precipitating Causes of Acute HF
Cardiac causes:
• Non-compliance with medicines
• Arrhythmia
• Ischemia or infarction (superimposed)
• Uncontrolled hypertension
• RHD, myocarditis, valvular dse, MR
• Endocarditis
!50

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. Precipitating Causes of Acute HF
Non-cardiac causes:
• Renal Failure (fluid overload)
• Anemia
• Pulmonary embolism
• Infection
• Delivery after pregnancy
• Lifestyle (stress)
!52

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. 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. 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. Effects of Digoxin of other
Cardiac Tissues
!56

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. 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. Interactions with K+, Ca++, Mg++
• Ca facilitates the effects of digitalis by
overloading of intracellular calcium stores.
• Digitalis-induced abnormal automaticity
!59

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. 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. 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. Drugs Without Positive Inotropic Effects
• Diuretics
• ACE inhibitors
• ARBs
• Aldosterone antagonist
• Beta blockers
• Vasodilators
!63

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. 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. 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. 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. 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. 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. 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

72. !72

73. Antianginal drugs
!73

74. Pathophysiology of Angina
!74

75. !75

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. 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. • Vasodilate
• Reduce rate
!78

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. 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. 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

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. Calcium Channel Blockers
• Tachyarrhythmias
– Diltiazem & verapamil
HPN
Amlodipine & nifedipine
!84

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. Beta blockers
• Contraindicated with:
– Asthma
– Severe bradycardia, AV dysfunction
– Severe LV dysfunction
– CHF NYHA IV
!86

87. Partial Fatty acid Oxidation (pFOX)
• Trimetazidine
• metabolic mediators, inhibit the fatty
oxidation pathway in the myocardium
!87

88. Ivabradine
• Activation of the If channel or the funny
bone channel
• Decreases the heart rate without the effect
of hypotension
!88

89. Other Drugs
• Sulfonylureas
• thiazolidinediones
!89