RAAS & RAAS antagonists 2011/2012

Renin-Angiotensin-Aldosterone System (RAAS) and RAAS

Antagonists
• ANGIOTENSINOGEN (α2-globulin synthesized by the liver- synthesis is stimulated by
estrogen, cortisol, thyroxin and angiotensin II).
↓
↓ Renin from JGA of kidney
↓
• ANGIOTENSIN I (Inactive)
↓
↓ ACE in the lung
↓
• ANGIOTENSIN II (Very active)
↓
↓Aminopeptidase
↓
• ANGIOTENSIN III (Less active)
↓
↓ Angiotensinase
↓
Inactive Peptides

N.B.: JGA= Juxta-Glomerular Apparatus.

ACE=Angiotensin Converting Enzyme. It is identical to "Kininase II" enzyme which
metabolizes bradykinin into inactive fragments.

• Renin:
Glycoprotein protease enzyme synthesized by JGA of the kidney.
• Factors that stimulate renin release include:
1. Sympathetic stimulation of β1-receptors.
2. Decreased renal blood flow (due to low COP and hypotension).
3. Low Na+ reaching distal convoluted tubules (Macula densa).
4. Prostaglandin I2.
• Factors that inhibit renin release:
1. Angiotensin II (-ve feedback).
2. α2-Agonists (clonidine, alpha-methyldopa, guanfacin, guanabenz).
3. β1-Blockers.

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RAAS & RAAS antagonists 2011/2012

Angiotensin II:
• Synthesis: see before.
• Mechanism of action:
Stimulates specific angiotensin receptors: AT1 (Gq-linked → activation of PLC →↑IP3 and
DAG→↑ Ca2+ and activation of protein kinases) and AT2 (in CNS and adrenal medulla).
• Actions:
1. Very potent V.C. of both arteries (pressor action) and veins. It is about 40 times more
potent than noradrenaline.
2. Stimulates synthesis and release of aldosterone from adrenal cortex causing Na+ and
water reabsorption and K+ secretion in urine.
3. Stimulates release of catecholamines from adrenal medulla and stimulates
transmission in sympathetic ganglia.
4. Positive inotropic action.
5. Spasmogenic action on smooth muscle fibres.
6. Inhibits renin release (-ve feedback) and increases angiotensinogen synthesis.
7. Stimulates drinking (dipsogenic action), ↑ACTH and ADH (vasopressin).
8. Hypertrophy and mitogenic action on the cardiac muscle and blood vessels.

N.B.: Actions 1, 2, 3, and 4 lead to elevation of ABP.

• Therapeutic use:
Treatment of severe hypotension given by I.V.infusion; especially if hypotension is due to
overdose of α1-blockers (α-agonists as noradrenaline and phenylephrine are not
effective, whereas adrenaline will lead to more hypotension..Why?).

Antagonists of the Renin-Angiotensin System:

a) Inhibitors of renin release:

• β-Blockers (both non-selective and cardioselective).
• α2-Agonists (Clonidine-Guanfacin-Guanabenz-α methyldopa).

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RAAS & RAAS antagonists 2011/2012

b) Angiotensin Converting Enzyme Inhibitors

(ACE inhibitors-ACEIs)

• Chemistry:
1. Sulphhydryl-containing: Captopril –Active drug.
2. Non-SH -containing:
a) Lisinopril: Active drug.
b) Enalapril-Ramipril-Perindopril-Fosinopril-Benazepril-Quinapril: Prodrugs

• Pharmacokinetics:
1. Absorption:: Well absorbed orally, oral absorption of ACEIs is reduced by antacids.
Captopril is affected by presence of food, so it is better given on empty stomch (1-2
hours before meals).
Enalaprilat is also given I.V. in emergency hypertension.
2. Distribution: Pass placental barrier and are fetotoxic (teratogenic).
3. Fate:
a) Captopril (active drug) is partly metabolized by the liver into inactive metabolites
(50%) and partly excreted unchanged in urine (50%).
b) Lisinopril (active metabolite) is mostly excreted unchanged in urine, and so it has a
long half-life.
c) Most ACEIs are prodrugs: converted into active metabolites by the liver, e.g.
Enalapril is converted into enalaprilat, and these active metabolites are excreted in
urine, except Fosinopril which is excreted in bile, and it can be given in renal
impairment without dose adjustment.

• Pharmacodynamics:
Mechanism of action:
1. Inhibit ACE leading to reduction of conversion of AT-I (inactive) into AT-II (the most
active angiotensin).
2. Inhibit inactivation of kinins (as bradykinin) resulting in accumulation of kinins which
induce powerful vasodilatation by: stimulation of vasodilator prostaglandin synthesis
as PGI, and by releasing nitric oxide.

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RAAS & RAAS antagonists 2011/2012

Pharmacological actions:
1. V.D. of both arteries and veins (decreases after-load and pre-load; respectively).
N.B. ACEIs increase renal blood flow but may reduce glomerular filtration due to
dilatation of the efferent arterioles more than the afferent arterioles which decrease
intra-glomerular pressure.
2. Reduction of aldesterone synthesis and release → excretion of Na+ and water in urine,
and retention of K+(hyperkalemia).
3. Reduction of catecholamine release from adrenal medulla.
4. Reduction of bradykinin metabolism by inhibition of kininase II leading to
accumulation of bradykinin which causes potent V.D. but also produces dry persistent
cough due to its inflammatory reaction in the lung.
5. Reduction of sympathetic activity by decreasing release of adrenaline and
noradrenaline from the adrenal medulla and from adrenergic neurons, and inhibition
of transmission in sympathetic ganglia.
6. Decrease the positive inotropic action induced by AT-II.
(All previously mentioned actions ↓ABP).
7. Inhibit the mitogenic action and remodeling induced by AT-II.
8. Increase renin (no –ve feedback) but decreases angiotensinogen.

• Therapeutic uses:
1. Hypertension especially in:
a) Diabetic patients (drugs of choice, why?).
b) Hypertensive with heart failure.
c) High renin.
2. Congestive heart failure (decrease both pre-load and after-load).
3. To prevent remodeling after myocardial infarction.
4. Diabetic nephropathy.

• Advantages of ACEIs:
1. Mild venodilatation which explains the following:
a) The venous return, EDV, and COP are not markedly decreased. COP is maintained
and even increases in patients with heart failure.
b) No postural hypotension (except after the first dose).
2. No reflex tachycardia (due to reduction in sympathetic activity).
3. No change in blood glucose, no hyperuricemia, and no hyperlipidemia in contrast to
other antihypertensive drugs as beta blockers and thiazides and loop diuretics.

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RAAS & RAAS antagonists 2011/2012

• Adverse effects:
1. 1st dose phenomenon: severe postural hypotension after the first dose especially in
sodium-depleted patients (due to the use of diuretics).
Avoided by starting treatment with small doses and giving the first dose at bed-time
(remember selective α1-blockers as prazosin). Diuretics may be stopped before
administration of ACEIs.
Treated by: saline (NaCl) IV infusion or oral salt intake.
2. Allergy (skin rash, angioneurotic edema, and rarely hepatotoxicity); especially
captopril (SH-containing).
3. Dry persistent cough.
4. Hyperkalemia especially in renal impairment.
5. Neutropenia.
6. Proteinurea (in large doses).
7. Dysgeusia (impaired taste sensation).
8. Fetotoxicity (teratogenicity) if ACEIs are administered in first trimester, and fetal
hypotension, fetal growth retardation, renal hypoplasia, oligohydramnios, and even
fetal death if they are given in second and third trimester.
9. Acute renal failure in "bilateral renal artery stenosis".

• Contraindications:
1- Pregnancy. 2- Bilateral renal artery stenosis.
3- Allergy. 4- Bronchial asthma.

• Drug interactions:
a) Pharmacokinetic interaction: Antacids decrease oral absorption of ACE inhibitors.
b) Pharmacodynamics interactions:
1. NSAIDs antagonize the antihypertensive effect of ACE inhibitors (due to inhibition
of bradykinin synthesis and due to Na+ and water retention).
2. With thiazide and loop diuretics: Synergism and maintain serum K+ normal.
However, they may aggravate first dose phenomenon if they cause severe
hyponatremia.
3. With K+-sparing diuretics and non-selective Beta blockers: Severe hyperkalemia
may occur.

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RAAS & RAAS antagonists 2011/2012

c) Angiotensin Receptor Blockers (ARBs):

• Examples: Losartan, Valsartan, Candesartan, Telmisartan, Irbesartan.

• They are non-peptides and are given orally.
• They are competitive antagonists with AT II on AT1-receptors.
• Actions are identical to ACE inhibitors but they do not lead to accumulation of bradykinin
(because they do not inhibit kininase II).
• Uses: as ACEIs.
• Adverse effects: as ACE inhibitors Except cough, and less allergic reactions especially
angioneurotic edema.
• Drug interactions: ARBs correct the adverse effects caused by thiazides and loop
diuretics (hypokalaemia, hyperuricemia, and hyperglycemia).
N.B.:
1. ARBs inhibit release of noradrenaline from adrenergic nerves by blocking presynaptic AT1
receptors.
2. Saralasin: is a peptide so not given orally, given by I.V. injection – Partial agonist – not
used in treatment of hypertension but may be used to test the role of AT II in
hypertensive patients (it causes marked hypotension in high renin hypertension).

d) Renin Receptor Blockers:

as Aliskiren, Remikiren, and Enalkiren. They are used in treatment of hypertension, either
alone (monotherapy) or combined with diuretics. They may cause diarrhea.

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RAAS & RAAS antagonists 2011/2012

AT II ACEIs (Captopril) and ARBs (Losartan)

1. Stimulates AT1 receptors. 1. ACEIs inhibit conversion of inactive AT I
into very active AT II.
ARBs competitively block AT1 receptors.

2. V.C. of arteries (more) and veins 2. V.D.of arteries (more) and veins (less),
(less), leading to increase in afterload leading to decrease in afterload and
and preload. preload.

3. Stimulates aldosterone synthesis and 3. Inhibit aldosterone synthesis and release

release leading to sodium and water leading to sodium and water excretion
reabsorption and potassium and potassium retention (hyperkalemia).
excretion.

4. Positive inotropic action. 4. Inhibit positive inotropic action of AT II.

5. Sympathetic stimulation. 5. Decrease sympathetic activity.

6. Elevates ABP. 6. Decrease ABP.

7. Hypertrophy of cardiac muscles but 7. Prevent hypertrophy and remodeling of

may lead to remodeling. cardiac muscles (cardioprotective action).

8. Inhibits renin release (negative 8. Increase renin release.

feedback).

9. Other actions: spasmogenic on SMF- 9. Other actions: ACEIs-but not ARBs-lead to

Dipsogenic-stimulates ADH and ACTH- accumulation of bradykinin by inhibition
stimulates angiotensinogen synthesis. of its degradation.

10.Used to elevate ABP in cases of severe 10.Uses: Hypertension-CHF-Diabetic

hypotension especially due to alpha nephropathy-After myocardial infarction.
blockers, given by IV infusion
(peptide).

7 Dr.Ahmed Abdel Rahman www.medadteam.org