Angiotensin Antagonists

Renin-Angiotensin-AldosteroneSystem RAAS -

Pharmacology ‫פרופ' ג'ריס יעקוב‬ ‫ פנימית‬-‫מרכז רקנאטי‬ ‫ רמב"ם‬- ‫טכניון‬

Renin Angiotensin Aldosterone System = RAAS

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One the most important regulatory systems: Extrinsic (renal/hepatic) Intrinsic local tissue production (brain, heart) It is pharmacologically well developed:   

Hemodynamics Volume determination Growth Effects

Renin-Angiotensin System Angiotensinogen

Asp Arg Val Tyr Ile His Pro Phe His Leu Val Ile His Asn R

Renin Angiotensin I

Asp Arg Val Tyr Ile His Pro Phe His Leu

Angiotensin Converting Enzyme-1 Angiotensin II

Asp Arg Val Tyr Ile His Pro Phe

Aminopeptidase Angiotensin III Peptide fragments

Arg Val Tyr Ile His Pro Phe

Angiotensinases various peptidase

Renin-Angiotensin-Aldosterone System Sensory Inputs, primarily in Kidney Renin Angiotensinogen

ACE-1 Angiotensin I Angiotensin II

Increased Blood Pressure (multiple mechanisms)

Aldosterone Na+ Reabsorption & K+ Excretion

ACE-2 Angiotensin 1-7

Increased Growth of Vascular and Cardiac Muscle

:Angiotensinogen 

Glycoprotein ~60.000 (15% carbohydrates)

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High Molecular weight (~ 400.000 with other proteins)

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Source: Liver, Liver and locally in kidney, Brain and fat

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tissue Plasma levels are correlating with BP values Released from the liver spontaneously and is induced by:      

Inflammation Insulin Estrogen, OC, Pregnancy (> x5-- involved in HTN) Glucocorticoids Thyroid hormones AII

Renin :((protease enzyme 

Prorenin (406 AA), Renin (340 AA)

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Juxtaglomerular System: granular

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cells Exocytosis into the afferent arterioles Prorenin: renin, 10 : 1 T1/2 = ~ 15 minutes Stimuli………………..

Juxtaglomerular Apparatus 

Juxtaglomerular apparatus is a sensor, for the regulation of BP and blood volume

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BP sensed by stretch receptors in the afferent arteriole

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Na Delivery to the distal tubule is sensed by macula densa

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Both, regulate the secretion of renin from granular cells in the juxtaglomerular apparatus

Renin Secretion Sympathetic NS NE

ß1-AR

Macula Densa [Na+] Na-K-2Cl

Renal Baroreceptor

BP afferent arteriole

(NO & COX2) Adenosine, PGs Stretch receptors

Juxtaglomerular Cell cAMP

RENIN

(-)

Angiotensin AT1receptor

Renin Pharmacology:    

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Renin blocker SNS activity reducers Beta-1 Blockers PGs production blockers AT1-antagonists Adenosine (A1) Drugs affecting [Na] Drugs affecting BP – indirect effects

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Aliskiren (new) Clonidine Metoprolol, bisoprolol NSAIDs, (COX2blocker) Losartan inhibits secretion Diuretics (+) renin Drugs by reducing BP (+) secretion

The Renin-Angiotensin System Angiotensinogen

Asp Arg Val Tyr Ile His Pro Phe His Leu Val Ile His Asn R

Renin Angiotensin I

Asp Arg Val Tyr Ile His Pro Phe His Leu

Angiotensin I is rapidly metabolized to AII Has mild pressor effect

Renin-Angiotensin System Angiotensinogen

Asp Arg Val Tyr Ile His Pro Phe His Leu Val Ile His Asn R

Renin Angiotensin I

Asp Arg Val Tyr Ile His Pro Phe His Leu

Angiotensin Converting Enzyme-1 Angiotensin II

Asp Arg Val Tyr Ile His Pro Phe

AII is the principal active peptide of the RAAS system T1/2 15-30 seconds (destroyed by angiotensinases) One of the most potent vasoactive peptides Acts on AT1 (alpha & beta) and AT2 receptors

A Simplified Scheme of the Renin-Angiotensin System

ACE-1 Endothelial cells membrane Systemic vasculature Lung location mainly MW: 170.000 1277 AA Zinc is essential for its activity

Boehm M and Nabel E. N Engl J Med 2002;347:1795-1797

Dual Role of ACE in blood pressure regulation ACE-1

Angiotensin

Bradykinin

Vasoconstriction, Increased BP

Vasodilation, Decreased BP

Formation of Angiotensins and Organs Affected by Their Actions

Goodfriend T et al. N Engl J Med 1996;334:1649-1655

Angiotensin II, Receptors 

Four

types of angiotensin receptors (1,2,3

and 4) 

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AT1 and AT2 are the most important AT2 is important during fetal stage

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AT2

its expression is low in healthy subjects

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AT2

its role in the adult cardiovascular

system is not well established

A II types 1 (AT 1 ) and 2 (AT 2 ) receptors Opposing effects

Angiotensin II actions Peripheral resistance  Potent vasoconstrictor  Enhances NE release in the periphery  Decreases NE uptake  Increases central SNA  Increases Adrenaline release  Vasopressin Expression of proto-oncogenes release structure

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Renal function Na reabsorption in PT Releases Aldosterone Alters renal hemodynamics Vasoconstriction of afferent and efferent arteriole Thirst (AIII) Cardiovascular

Increase growth factors Extracellular protein matrix Vascular hypertrophy and cardiac remodelling

Role of Angiotensin II and Mechanical Stress in the Generation of Reactive Oxygen Species in the Vessel Wall in Patients with Hypertension

Sowers J. N Engl J Med 2002;346:1999-2001

Mechanisms of angiotensin II (ANG II)-dependent, oxidant-mediated vascular damage

ACE-Inhibitors Angiotensinogen

Asp Arg Val Tyr Ile His Pro Phe His Leu Val Ile His Asn R

Renin Angiotensin I

Asp Arg Val Tyr Ile His Pro Phe His Leu

ACEInhibitors Block the production of AII Increase Concentration of AI and renin Increase concentration of angiotensin 1-7 by endopeptidase (BP, function ??) Increase bradykinin and therefore PGs production (effective BP drop ?)

Classical ACE-inhibitors liver

Captopril ------

Bioavailabil ity

T-1/2

Elimination

75%

2h

Kidney

11 h

Kidney

Enalapril

enalaprila t

60%

Ramipril

ramiprilat

50-60% ? > 18 h

Liver &

kidney Ramipril has 3-phase elimination plasma, tissue dissociation

ACE-I clinical indications      

Hypertension Left ventricular dysfunction & CHF Diabetic nephropathy Nephrotic syndrome Renal artery stenosis No difference exists between the various ACE-I

ACE-inhibitors side effects           

Hypotension avoided by titration of dosing Hyperkalemia Renal failure Proteinuria Cough: bradykinin ? (1wk-6 mo) Angioedema: bradykinin Potential teratogenicity Liver abnormal function Dysgeusia Anemia, neutropenia Protective against diabetes mellitus !

AT1 Receptor Blockers (ARBs) Highly selective 10000:1 (AT1:AT2)  Competitive antagonists  ARBs are more effective in blocking AT1 compared to ACE-I  Allow activation of AT2  Circulating AII levels are very high  Angiotensin 1-7 is less available  ARBs do not affect bradykinin metabolism Which is more effective, ARBs or ACE-I ??? 

AT1 Blockers Peak

T-1/2

Elimination

Candesart 3-4 h < 50% 9 h an Exp 3174 metabolite < 50% Losartan 2-9 h 15%:

70% Liver Liver CYP450 Liver

more potent

Valsartan

Bioaviabilit y

active metabolite

2-4 h < 50% 9 h

Protein binding is about 90% for all

ARBs therapeutic use      

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All are approved for hypertension Congestive heart Failure (not all) Diabetic nephropathy (not all) Effective in reducing stroke Could be combined with ACE-I Combined ACE-I and ARBs in nephrotic syndrome More effective in reducing LVH in HTN

:ARBs Side Effects    

No angioedema No cough Much less skin eruptions Otherwise similar profile to ACE-I group.

Physiologic and Pathophysiologic Effects of Aldosterone on the Kidney and Heart in Relation to Dietary Salt Levels

Aldosterone Antagonists: spironolactone, eplerenone Dluhy R and Williams G. N Engl J Med 2004;351:8-10