1) The document discusses the renin-angiotensin-aldosterone system and its role in regulating blood pressure. 2) Angiotensin-converting enzyme inhibitors (ACEIs) work by preventing the conversion of angiotensin I to angiotensin II, thereby lowering blood pressure. 3) ACEIs, beta blockers, and aldosterone antagonists have been shown to reduce mortality in patients with heart failure by 23%, 35%, and 30% respectively over 2 years.

1. Dr Abida Shaheen

9. Blood Pressure =
Cardiac Output X Peripheral Resistance
Preload Contractility Vasoconstriction
Heart Rate Venous Arteriolar Venous
Circulating
Fluid Volume
Renin
Renal Sympathetic Vascular
Angiotensin
Sodium Nervous Smooth
Aldosterone
Handling System Muscle
System
Vascular remodeling

10. Afterload
α2 Vasomotor center
Volume
Kidneys Cardiac Output
β1 Heart
Renin
β1
V
V
Ang I
Preload
Ang II
BP= CO x TPVR β2 α1
Aldosterone
VSMCs
Vascular
Resistance arterioles Capacitance venules
Smooth
Muscle
Cells
TPVR
Total Peripheral Vascular Resistance (TPVR)

12. Sites of action of antihypertensive drugs

13. Renin-Angiotensin-Aldosterone System
Angiotensinogen
Renin
Angiotensin I
ACE
Angiotensin II
↑ Aldosterone AT I ATII
Vasoconstriction
↑ Blood Pressure

14. Angiotensin Converting
Enzyme
Kininogens Angiotensinogen
Kallikrein Renin
Angiotensin I
Bradykinin
ACEIs
ACEIs ACE
Angiotensin II
Inactive Peptides
BK receptors
AT-1 receptors

15. Angiotensin II

16. Pathophysiologic role of Angiotensin II
Angiotensin Receptor Angiotensin II
Blocker
ARB
AT1 Aldosterone
Vasoconstriction Receptor Production
Cell Growth
Fibrosis ↑ Sodium/Water
↑ PVR
Retention
LVH
↑ BP Vascular ↑ BP
Remodeling

17. ACEIs : Prevention of renal disease
INTRAGLOMERULAR PRESSURE
Arterial
pressure
Angiotensin II Angiotensin II
+ + ++
Afferent 20 Efferent
mmHg
arteriole arteriole
excess glomerular
Bowman’s pressure
capsule
hyperfiltration
microalbuminuria

18. Aldosterone Plays a Multi-factorial CV Role
Angiotensin II–K+ –ACTH- Norepinephrine – Serotonin – Endothelin-NO
Aldosterone
Kidneys Brain Blood Vessels Heart
+SNS
Na+ reabsorption ↑ Blood Cytokine Activation
K+ excretion Pressure Vascular Inflammation Cardiac Hypertrophy
Endothelial Dysfunction Myocardial fibrosis
Hypertension Vascular Injury LV Hypertrophy
Ventricular Remodeling
End-stage renal disease, MI, HF, Arrhythmias

19. Neurohormonal Activation in
Heart Failure
Angiotensin II Norepinephrine
Disease Progression
Hypertrophy, apoptosis, ischemia,
arrhythmias, remodeling, fibrosis

20. Effect of ACE Inhibition
↑ Angiotensin II ↑ Norepinephrine
ACE inhibitor
Disease Progression
Hypertrophy, apoptosis, ischemia,
arrhythmias, remodeling, fibrosis

21. Effect of β-Blockade
↑ Angiotensin II ↑ Norepinephrine
β-Blockade
Disease Progression
Hypertrophy, apoptosis, ischemia,
arrhythmias, remodeling, fibrosis

22. Effect of ARB
↑ Angiotensin II ↑ Norepinephrine
ACE Inhibitor β-Blockade
ARB
Disease Progression
Hypertrophy, apoptosis, ischemia,
arrhythmias, remodeling, fibrosis

24. Figure 11.7

25. Beta Blockers
Mechanisms of Action
 Effects on myocardium
Suppression of renin release
Inhibition of presynatic β 1 receptors positive
feeback
Decreased central sympathetic outflow
CNS effects
Reduction in peripheral resistance
Improvement in vascular compliance
Resetting of baroreceptor levels
Attenuation of pressor response to catecholamines
(stress, exercise)

26. Beta Blockers
 Hypertension
 Angina pectoris
 Myocardial Infarction
 Arrhythmias
 Heart Failure
 Conditions associated with sympathetic overactivity
 Migraine prophylaxis
 Perioperative Hypertension

27. Beta Blockers
Side Effects
 Bronchospasm
 Bradicardia/heart block
 Mask and prolong the symptoms of hypoglycemia
 Abrupt withdrawal can precipitate MI
 Cold extremities, Raynaud’s phenomenon, intermittent claudication
 Decreased exercise tolerance; fatigue, depression and impotence
 CNS: sleep disturbance, vivid dreams, nightmares
 Effects of plasma lipids

29. Without Compelling
Indications
Stage 1 Hypertension Stage 2 Hypertension
(SBP 140–159 or DBP 90–99 (SBP >160 or DBP >100 mmHg)
mmHg) 2-drug combination for most
Thiazide-type diuretics for most. (usually thiazide-type diuretic and
May consider ACEI, ARB, BB, CCB, ACEI, or ARB, or BB, or CCB)
until goal blood pressure is achieved
or combination.
Optimize dosages or add additional dru
Blood Pressure
Not at Goal
Initial Drug Choices
Lifestyle Modifications
as needed.
(diuretics, ACEI, ARB, BB, CCB)
Not at Goal Blood Pressure (<140/90 mmHg)
Other antihypertensive drugs
indications
Drug(s) for the compelling
(<130/80 mmHg for those with diabetes or chronic kidney disease)
Indications
With Compelling
Algorithm for Treatment of Hypertension

31. Classification of Heart Failure
ACC/AHA HF Stage1 NYHA Functional Class2
A At high risk for heart failure but without
structural heart disease or symptoms
of heart failure (eg, patients with
hypertension or coronary artery disease)
I Asymptomatic
B Structural heart disease but without
symptoms of heart failure
II Symptomatic with moderate exertion
C Structural heart disease with prior or
current symptoms of heart failure
III Symptomatic with minimal exertion
D Refractory heart failure requiring IV Symptomatic at rest
specialized interventions
1
Hunt SA et al. J Am Coll Cardiol. 2001;38:2101–2113.
2
New York Heart Association/Little Brown and Company, 1964. Adapted from: Farrell MH et al. JAMA. 2002;287:890–897.

32. Stages of Heart Failure and Treatment Options for Systolic Heart Failure
Jessup, M. et al. N Engl J Med 2003;348:2007-2018

33. Therapies Relative Risk Mortality
Reduction 2 year
ACE-I 23% 27%
Β-Blockers 35% 12%
Aldosterone 30% 19%
Antagonists
ICD 31% 8.5%