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Pharmacology of Raas

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12 views22 pages

Pharmacology of Raas

Uploaded by

suzannantumbwe94
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© © All Rights Reserved
We take content rights seriously. If you suspect this is your content, claim it here.
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PHARMACOLOGY OF THE

RENIN AAS
Role of RAAS in Hypertension (HT)

• Renin, Angiotensin & Aldosterone play important


roles in the pathogenesis of HT

  20% of patients with essential HT have


inappropriately high plasma renin activity

• BP of patients with high-renin HT respond well


to:
 -adrenoceptor blockers ( ↓plasma renin activity)
– Angiotensin inhibitors
Activation & Effects of RAAS
BP Regulation
• Renin – Angiotensin-Aldo Mechanism
• Stimulation of the Juxtaglomerular Apparatus by
e.g:
– ↓ GFR
– ↓ Na+ and ↑ K+ levels in blood

 Renin release
– Causes conversion of angiotensinogen to angiotensin

Angiotensin Converting Enzyme (Kininase II)


– In the lungs & blood vessels converts Ang I to II
Comparison of BP regulation by the BRR & RAAS
Physiologic effects of Ang II
• Vascular
– Smooth m – vasoconstriction, hypertrophy, hyperplasia
– Endothelium - ↓NO production
– Connective tissue – extracellular matrix synthesis

• Myocardium
– Hypertrophy

• Adrenal gland
– medulla – to release epinephrine
– cortex – to release aldosterone
– fasciculata - cortisol
Physiologic effects of Ang II
• Posterior pituitary gland
– ADH release

• Kidney
– Embryogenesis
– Efferent vasoconstriction

• Sympathetic neurons
– NE release
Receptor mechanisms for Ang II

• 2 well characterised receptors: AT1 & AT2


• Effects mediated mainly by AT1

Signal transduction:
• Ang II binds to AT1
 coupling to & dissociation of cell membrane associated G-
protein
 activation of PLC causing cleavage of phosphoinositides
( i.e. IP3 & DAG)
 release of Ca2+ from intracellular stores
activation of protein kinases
 phosphorylate & activate effector proteins in target cells.
Effects of ALDO
Aldosterone
• Increases reabsorption of Na+ / excretion
of K+ in late distal convoluted tubule
• Water reabsorption in collecting ducts
Drug Classes

• 1) Renin Inhibitors

• 2) Angiotensin Converting Enzyme


Inhibitors (ACEIs)

• 3) Angiotensin Receptor Blockers


(ARBs)
1. Renin Inhibitors

• Renin antibodies
• Analogs of prorenin (Remikrein Ro-42-
5892)
• Analogs of angiotensinogen ( Enalkrein –
A64662)
– Most are being developed; but have low
biovailability
– Mechanism: reduce plasma rennin activity.
2. ACE Inhibitors
Classification:
• 1) Sulfhydryls – Captopril
• 2) Dicarboxyls – Enalapril, Lisinopril, benazepril
• 3) Phosphorous containing – Fosinopril

Dosing:
• Captopril (capoten)
– Twice daily

• Benazepril (Lotensin)
– 1 or 2 doses

• Enalapril (Vasotec) –( once daily)

• Lisinopril (Prinivil, Zestril) -Once daily


ACEIs – Mechanism & Pharmacological effects

• Inhibit ACE (kininase II), a peptidyl


dipeptidase
 ↓ conversion of Ang I to Ang II
 Increase bradykinin
 NO, PGE2, & PGI2
– Results in ↓vasoconstriction & dilation
– Prevents release of Aldosterone
– Reduces Na+ reabsorption
– Retention of K+
ACEIs – Pharmacological effects cont’d

• Cause efferent arteriole dilation


– Reduces intra-glomerular pressures
– Protects kidney from high pressure
– Slows deterioration of GFR
– Reduces proteinuria

• Improves morbidity of DM nephropathy


• Improves response of cells to insulin
• No elevation of lipids
– Good choice in the Metabolic syndrome
ACEIs - Adverse effects

• Cough – caused by inhibition of Kininase II which


degrades histamine and bradykinin
– Resolves with DC of drug

• Angioedema
• Hypotension with Na+ depletion
• Rare cholestatic jaundice / hepatic necrosis –
mechanism???
• Category D (esp in 2nd / 3rd trimesters – fetal injury /
death
• Don’t use with K+ sparing drugs - hyperkalemia
ACEIs – Therapeutic Indications

• Hypertension

• Proteinuria (from HTN or DM)

• Heart failure – reduces mortality

• Myocardial Infarction – reduces mortality

• Atherosclerosis or diabetes –HOPE trials – reduction in MI,


stroke, death

• DM – increase insulin sensitivity (HOPE)


3. Angiotensin II Receptor Blockers (ARBs)

Drug Examples

1) Orally active
• Losartan (Cozaar)
• Valsartan (Diovan
• Irbesartan (Avapro)
• Candasartan (Atacand)
• Eprosartan (Teveten)

2) Parenteral – Saralasin (used only in research)


ARBS- Mechanism of action

• Competitive inhibitors of Ang II at the AT1 receptor.


– Blocks the effects of angiotensin II after it is formed

• No cough (Kininase II not inhibited)


• No allergic reaction
• Receptors specifically in vascular smooth muscle
• Reduce PVR without reflex CO, HR, & contractility
• Improve insulin sensitivity
• Reduce plasma catecholamines
ARBs - Clinical aplications & adverse effects

Therapeutic Uses
• Hypertension
• Congestive Heart failure
• Diabetic Nephropathy

Adverse effects
• Few adverse effects
• Low incidence of cough,allergic reactions
&angiodema
• However do cause:
– Fetal renal toxicity
– hyperkalemia
Study question
• Discuss the role of the RAAS in the regulation of
blood pressure and electrolyte balance. With this
in mind, mention ANY FOUR classes of drugs
that modulate this system, their mechanism of
action, therapeutic uses, and adverse effects.

• ACE inhibitors and ARBS are not recommended


in pregnancy. Why?

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