Renin-Angiotensin-Aldosterone

System Blockers

Layla Borham
Renin Angiotensin System

Dr. Layla Borham

 Angiotensin-II plays a central role in
organ damage
Atherosclerosis* Stroke
Vasoconstriction
Vascular hypertrophy
Endothelial dysfunction Hypertension

A-II AT1 LV hypertrophy

receptor Fibrosis
Remodelling Heart failure DEATH
Apoptosis MI

GFR
Proteinuria
Renal failure
Aldosterone release
Glomerular sclerosis

Dr. Layla Borham

 Blockade of Renin-Angiotensin-Aldosterone System
• Angiotensin converting enzyme (ACE) inhibitors

 Captopril

 Enalapril (prodrug) anything else ending in -pril

– (lisinopril, trandolapril, fosinopril, perindopril,

quinapril, etc)

• Angiotensin II receptor (AT1) antagonists

 Valsartan, Losartan, Candesartan, irbesartan, others ending

in -sartan
• Renin Inhibitors: Aliskiren
Dr. Layla Borham
Dr. Layla Borham
 Angiotensin Converting Enzyme Inhibitors
Cardio-renal Effects of ACE Inhibitors
• Vasodilation (arterial and venous) (blocking angiotensin II
formation and inhibiting bradykinin metabolism)
- reduce arterial and venous pressure
- reduce ventricular afterload and preload
• Decrease blood volume (blocking the effects of angiotensin II
in the kidney and by blocking angiotensin II stimulation of
aldosterone secretion)
- natriuretic and diuretic
• Depress sympathetic activity
• Inhibit cardiac and vascular hypertrophy
Dr. Layla Borham
 ACE-Inhibitors in Hypertension
• Produce effective control of hypertension with less adverse effects on
“quality of life” measures

• ↓ BP principally by ↓ peripheral and renal vascular resistance.

• No orthostatic hypotension (captopril does not interfere with
sympathetic function).

• No reflex sympathetic activation and cardiac output and heart rate

are not significantly changed, and can be used safely in persons
with ischemic heart disease.

• The absence of reflex tachycardia may be due to:

1. downward resetting of the baroreceptors.

2. enhanced parasympathetic activity. Dr. Layla Borham

 ACE-Inhibitors in Hypertension
• Are advantageous in management of hypertensive
diabetic patients.
• Antihypertensive drug of choice in treatment of
hypertensive patient who have hypertrophic left
ventricles, and in patients who have ischemic heart
disease with impaired left ventricular function.
• ACE inhibitors have also proved to be extremely useful in
the treatment of heart failure, and after myocardial
infarction.

Dr. Layla Borham

ACE-Inhibitors in Hypertension

Dr. Layla Borham

 ACE Inhibitors and Heart Failure
• There is good evidence that they reduce mortality,
hospital admission, and improve symptoms and exercise
tolerance in all grades of symptomatic heart failure
(NYHA class II-IV).
• They also delay progression of asymptomatic left
ventricular systolic dysfunction to symptomatic disease.
• ACE inhibitors should be considered in all patients with
left ventricular systolic dysfunction, who do not have
contraindications
Dr. Layla Borham
 ACE Inhibitors and Heart Failure
Enalapril, lisinopril, captopril
• They reduce the amount of angiotensin II produced.
• ACE inhibitors can afford both hemodynamic improvement as
well as disease modifying benefits in CHF "and have favorable
effects on heart remodeling and survival," and that these drugs
produce long-term benefits.
• Decreases both preload and afterload. Reduction of aldosterone
decrease blood volume (secondary to a decrease in Na+ and water
retention)
• They have a favorable side effect profile.
Dr. Layla Borham
 ACE Inhibitors and Heart Failure
• Reduces sympathetic tone, which may further decrease PR.
• Are first single-line therapy in patients with mild left
ventricular heart failure. They improve symptoms, slow
progression of the disease, reduce mortality, and decrease the
incidence of hospitalization.
• ACE inhibitors reduce the normal aldosterone response to
sodium loss. Therefore, the use of ACE inhibitors enhance the
efficacy of diuretic treatment, allowing the use of lower diuretic
dosages and improving control of hypertension.
• Reduction in aldosterone production by ACE inhibitors also
affects potassium levels.
Dr. Layla Borham
 ACE Inhibitors
• Conclusively demonstrated in CHF patients to reduce
– morbidity Sustained augmentation of
parasympathetic tone with angiotensin-
– Mortality
converting enzyme inhibition in patients
with CHF
• Post MI patients to reduce
– morbidity ACE Inhibitors also reduce plasma
norepinephrine levels and NE -induced
– mortality
vasoconstriction
– onset of heart failure

Dr. Layla Borham

 Adverse Effects
1. Angioedema, (due to increase in bradykinin).
2. Dry cough, wheezing, decrease taste.
3. ACE inhibitors are contraindicated during pregnancy (Fetal toxic
effects and malformations).
4. Renal failure, especially in bilateral renal artery stenosis.
5. Initial dose of an ACE inhibitor may precipitate an excessive
hypotensive response (in volume depleted patients).
6. Proteinuria, neutropenia, allergic manifestations.
7. Hyperkalemia.
8. Drug interaction: nonsteroidal anti-inflammatory agents
(precipitate acute renal failure), potassium sparing diuretics
(spironolactone) or potassium supplements  hyperkalemia.
Dr. Layla Borham
 Different roles of AT1 and AT2 receptors

Angiotensin II

AT1 AT2

1. Vasoconstriction 1. Vasodilatation
2. Vascular proliferation
2. Anti-proliferation
3. Aldosterone secretion
4. Cardiac myocyte proliferation 3. Apoptosis
5. Increased sympathetic tone Dr. Layla Borham
 Angiotensin Receptor Blockers
Valsartan, Losartan, Candesartan, irbesartan.
• Competitive receptor antagonist of angiotensin II at AT1
receptor.
• Relax smooth muscle and thereby promote vasodilatation,
increase salt and water excretion, ↓ plasma volume.
• They are effective in the treatment of heart failure.
• At present recommended for use in ACEIs intolerant
patients.
• Some suggestion that they may have benefit when added
to ACEIs.
Dr. Layla Borham
 Angiotensin Receptor Blockers

Side Effects:

1. Well tolerated; low incidence of dizziness.

2. Hyperkalemia.

3. Angioneurotic edema and cough associated with ACE

inhibitors have not been seen with this agent.

4. Contraindicated in second and third trimester of pregnancy

and in patients with bilateral renal artery stenosis.

Dr. Layla Borham

 Aldosterone Antagonists
• Spironolactone
– Potassium sparing diuretic
– Inhibits the actions of aldosterone
– Used in combination with other diuretics

• Proven to reduce mortality when used in

combination with ACEIs.

Dr. Layla Borham

 Aldosterone Antagonists
• Spironolactone should be considered in patients with
moderate to severe heart failure (NYHA class III-IV)
who are symptomatic despite taking ACE inhibitors,
diuretics and/or digoxin.
• Hyperkalaemia and renal failure should be excluded
before starting spironolactone, and renal function and
potassium monitored regularly throughout treatment

Dr. Layla Borham