Transcript DR SHREETAL RAJAN NAIR The Renin Angiotensin Aldosterone System (RAAS)  Most important neurohormonal system that maintains vascular tone and fluid-electrolyte balance in our body 

DR SHREETAL RAJAN NAIR
The Renin Angiotensin Aldosterone
System (RAAS)
 Most important neurohormonal system that maintains
vascular tone and fluid-electrolyte balance in our
body
 Is involved in the pathophysiology of most
cardiovascular diseases and hence its importance
 Works through a negative feedback loop in our body
Pathophysiology of RAS
Factors stimulating renin release
 Low arterial blood pressure
 Decreased sodium concentration in the distal tubule
 Decreased blood volume
 Increased beta -1 sympathetic activity
Drugs influencing PRA
 Increasing PRA
 Decreasing PRA
 ACEI
 Adrenergic blockers
 ARBs
 Renin inhibitors
 Vasodilators
 Diuretics
DRUGS ACTING ON RAAS
 ACE Inhibitors
 Angiotensin receptor blockers
 Aldosterone antagonists
 Renin inhibitors
 New therapeutic pathways
Historical aspects
 ACE was initially discovered from the venom of pit
viper and named bradykinin potentiating factor and
later it was found that this kininase and ACE were the
same.
 Teprotide was the first ACEI to be synthezised
 But it had limitations
 Later , captopril was developed as the first ACEI in
1977
ACEI
 ACE inhibitors differ
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2.
3.
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in the chemical structure of their active moieties,
in potency,
in bioavailability,
in plasma half-life,
in route of elimination,
in their distribution and affinity for tissue-bound
ACE, and
in whether they are administered as prodrugs.
ACE Inhibitors
CLASSIFICATION
 Class I : Containing a sulfhydryl group
- Captopril ( proline derivative)
 Class II : Prodrugs
 Class III : Water soluble
- Lisinopril ( Lysine derivative )
ACEI
 Captopril is the prototype of the sulfhydryl-containing
ACE inhibitors; others are fentiapril, pivalopril,
zofenopril, and alacepril.
 In vitro studies suggest that the presence of the
sulfhydryl group may confer properties other than
ACE inhibition to these drugs, such as free-radical
scavenging and effects on prostaglandins
 In vivo no much benefit has been found
ACEI – salient features
 Captopril by itself is active and its metabolites are also
active
 Prodrugs by itself are not active and need to be
converted to the active diacids in the liver and
prodrugs have better bioavailability
 Lisinopril is active and is not metabolised and excreted
unchanged
 All ACEI are excreted exclusively via renal system
except fosinopril,spirapril and trandolapril which are
excreted via the biliiary system and feces.
ACEI – salient features
 Bioavailability : highest – captopril; least – perindopril
 Most prodrugs are carboxyl derivatives except
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fosinopril
Time to peak action – fastest captopril ( 1 hr)
Elimination t ½ - longest with ramipril (8-48 hrs)
ACEI with duration of action > 24 hrs :
enalapril,lisinopril,ramipril and perindopril
Captopril is the only ACEI to cross BBB but its clinical
significance is unknown
ACEI – pharmacokinetics in a nut
shell
Nancy J. Brown, MD; Douglas E. Vaughan, MD Circulation. 1998;97:1411-1420.
ACEI- hemodynamic effects
 ACEI are beneficial in many ways
 Prevents generation of angiotensin II
 Useful in conditions in which the renin angiotensin
system is dysregulated like essential hypertension and
renovascular hypertension
 Decreases the peripheral vascular resistance
 Fall in systolic and diastolic BP
 No effect on cardiac output
INDICATIONS OF ACEI
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Heart failure
Chronic heart failure due to any cause
AMI
Early phase
AMI with HF
Hypertension
Chronic Renal Disease
Diabetic nephropathy
Risk prevention
ACEI – other indications
Non – cardiovascular
1. Diabetic and non- diabetic nephropathy
2. Scleroderma crisis ( captopril test to diagnose
renovascular hypertension )
Adverse effects
Adverse effects
 First dose hypotension more in diuretic treated
patients
 Hyperkalemia more in patients with impaired renal
function and those taking potassium sparing diuretics
and NSAIDs
 Cough : occurs in patients within 1-8 weeks ; subsides
in 7-21 days after discontinuation ;not dose relatedearlier it was believed to be due to inhibition of
bradykinin degradation; now it is believed to be
mediated by substance P as kininase II is also believed
to be degrade substance P. More in women
Adverse effects
 Angioedema: the pathogenesis is found to be similar to
the cough;
cough and angioedema found in higher incidence in
those concomitantly using DPP IV inhibitors as DPP is
also responsible for substance P breakdown.
 Rashes,urticaria: do not need drug stoppage
 Dysguesia is a reversible alteration in the taste
sensation – found in captopril treated patients and
believed to be due to the sulfhydryl moiety
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Adverse effects
 Granulocytopenia and proteinuria very rare but warrant
withdrawal
 Headache,dizziness ,nausea and bowel upset- in 1-4 %
 ARF in bilateral RAS due to dilatation of efferent arterioles
and fall in GFR and hence contraindicated
 Fetopathic effects- 1st trimester produces cardiovascular
malformations ( PDA ) and 2nd and 3rd trimester
responsible for oligohydramnios, fetal calvarial hypoplasia,
fetal pulmonary hypoplasia, fetal growth retardation, fetal
death, neonatal anuria, and neonatal death and hence
contraindicated in pregnancy.
Interactions
 NSAIDs especially in elderly, taking diuretics and ACEI
 Potassium sparing diuretics/ on K+ supplements
 Antacids decrease absorption
 Reduce Lithium clearance and predispose to toxicity in
those taking lithium
 Caution in
Impaired renal function, hypovolemia or dehydration
Contraindications
 Bilateral RAS
 Pregnancy
 Hyperkalemia
 Known allergy or hypersensitivity
 Serum creatinine (>2.5 – 3.0 mg/dl ) arbitrary cut off
in patients with heart failure
Pharmacogenomics
 Found to be less effective in young and elderly blacks
because are found to have less PRA.
 Adding drugs which increase PRA like diuretics have found
to increase response to therapy
 An insertion (I)/deletion (D) polymorphism in the ACE
gene that correlates with ACE activity such that ACE levels
are highest in patients who are homozygous for the ACE D
allele, lowest in patients homozygous for the ACE I allele,
and intermediate in those who are heterozygous . Persons
with the D/D phenotype had subdued response to the
ACEI
 Angioedema more in whites.
Some new concepts in ACE
inhibition
 ACE inhibitors have also been shown to cause a central
enhancement of parasympathetic nervous
system activity in healthy volunteers and patients with
heart failure. This action may reduce the prevalence of
malignant cardiac arrhythmias, and the reduction in
sudden death .
 The ACE inhibitor enalapril has also been shown to
reduce cardiac cachexia in patients with chronic heart
failure. Cachexia is a poor prognostic sign in patients
with chronic heart failure
Some new concepts in ACE
inhibition
 ACE inhibitors are under early investigation for the
treatment of frailty and muscle wasting (sarcopenia)
in elderly patients without heart failure
 The lactotripeptides Val-Pro-Pro and Ile-Pro-Pro
produced by the probiotic Lactobacillus helveticus or
derived from casein have been shown to have ACEinhibiting and antihypertensive functions ( discovered
in Japan IN 1991)
ACEI in heart failure
 Panel A- ACEI in HF with
depressed EF in a post
AMI metaanalysis
 Panel B – ACEI in HF with
depressed EF including
postinfarction trials
(metaanalysis)
 Benefit from therapy is
seen very early and
persisted long term
Omapatrilat
 Omapatrilat was a novel antihypertensive agent that
inhibits both neutral endopeptidase (NEP) and
angiotensin converting enzyme (ACE).
 NEP inhibition results in elevated natriureticpeptide
levels, promoting natriuresis, diuresis, vasodilation, and
reductions in preload and ventricular remodeling.
 This was being promoted for CHF but was not approved by
the FDA due to angioedema safety concerns
Omapatrilat - trials
 The OVERTURE (Omapatrilat Versus Enalapril
Randomized Trial of Utility in Reducing Events) study:
Omapatrilat was as good as enalapril but not better
 In the OCTAVE (Omapatrilat Cardiovascular Treatment
Assessment Versus Enalapril) study 25,267 hypertensives
were randomised to Omapatrilat or enalapril and a
difference of approximately 3 mmHg in favour of
Omapatrilat was seen.
 Significantly more cases of angioedema were seen with
Omapatrilat in both trials.
IMPRESS randomised trial
 Comparison of vasopeptidase inhibitor, omapatrilat,
and lisinopril on exercise tolerance and morbidity in
patients with heart failure
 Showed a trend in favour of omapatrilat
ARBs
 The ARBs act on the next step in RAAS and they block the
angiotensin II receptor through which angiotensin II exerts
its effects
 Why the need of ARBs arose after ACEI ?
1. Clinical and experimental studies showed the initial
suppression of angiotensin II after the administration of
angiotensin-converting enzyme (ACE) inhibitors is later
reversed and returns almost to pretreatment levels.
 The ESCAPE phenomenon was hypothesized which was
strengthened by the discovery that angiotensin II can also
be generated through non-ACEs
2.
Increased incidence of adverse effects with ACEI
therapy
Advantages of ARBs over ACEI
 Do not interfere with degradation of bradykinin and
other ACE substrates
 More complete inhibition of AT1 receptor activation
 Indirect activation of AT2 receptor
 Other molecular effects apart from the receptor action
 Losartan was the first ARB to be synthezised and it
was a imidazole derivative
 All ARBs expect for losartan are highly selective for the
AT1 receptor. In fact, ARBs show 10,000–30,000 times
greater affinity for the AT1 receptor than for the AT2
receptor
 The majority of ARBs produce insurmountable
antagonism ( non competitive inhibition )
What is the advantage of AT1
receptor specificity ?
 AT2 receptor may be exposed to a higher
concentration of Ang II
 It increases the Ang II-induced AT2 receptor
stimulation which may cause anti-cell proliferation
and vasodilation
Other effects of ARBs
 Inverse agonism of AT1 receptor
 Anti platelet effects
 Anti – inflammatory effects
 Reduction in serum uric acid levels
Benefits of Inverse agonism
1. Sometimes AT1 receptors are mutated and have
constitutive activity which means the receptors can get
activated in the absence of its ligand
 Constitutive has also been found in wild type receptors
 Losartan,valsartan,olmesartan and candesartan have
significant inverse agonism
Benefits of inverse agonism
2. AT1 receptor mRNA levels are upregulated by
myocyte stretching over time
 Studies have demonstrated that the AT1 receptor is
activated by the mechanical stretching of cultured rat
myocytes and constriction of the transverse aorta in
angiotensinogen knockout mice without the
involvement of Ang II, and these adverse effects were
suppressed by an inverse agonist
Anti platelet effects
 Losartan has some degree of antagonistic action on the
thromboxane A2 receptor which is responsible for the
platelet antiaggregatory effects
Anti inflammatory effects
 Ang II induces inflammation in vasculature and
vascular remodeling, and subsequently promotes
atherosclerosis. Ang II stimulates monocyte
chemoattractant protein-1 (MCP-1), interleukin (IL)-8,
tumor necrosis factor-a and IL-6 production
 Decrease in MCP-1 levels seen with irbesartan and
losartan
 Increase in adiponectin expression seen with
irbesartan,losartan,candesartan and telmisartan
Anti inflammatory effects
 PPAR gamma activation with eprosartan – may be one
reason of preventing New Onset Diabetes(NOD), the
other being increased adiponectin levels
 Irbesartan and olmesartan act as antagonists of
chemokine receptors
Actions are independent of actions on the AT1
and AT2 receptors and suggest a molecular level of
action for the ARBs
Decrease in uric acid levels
 Compared with other ARBs, losartan, telmisartan and
irbesartan have been shown to reduce serum uric acid.
 These effects are believed to be mediated at the
molecular levels independent of action on the AT1
receptor
In a nut shell
Angiotensin II type 1 receptor blockers: class effects versus molecular effects
Shin-ichiro Miura, Sadashiva S. Karnik and Keijiro Saku -Journal ofthe Renin-Angiotensin-Aldosterone
System (Including other Peptidergic systems)
March 2011 Volume 12 Number 1
ARB in hypertension
ACC/AHA recommendations (2005)
The concept of dual RAAS
blockade with ACEI and ARB
 Arose because of the phenomenon of escape
phenomenon with ACEI
 To achieve complete and more effective blockade of
Angotensin action
 It was combining ACEI and ARB would be of benefit
but studies did not give promising results
 Now dual ACEI and ARB therapy not recommended
except in non- diabetic renal disease (COOPERATE,2003 trial showed progression of non
diabetic renal disease retarded to a greater extent than
with monotherapy.
Some salient features of ARBs
 Highest affinity for AT1 receptor – candesartan
 Longest duration of action - telmisartan
 All ARBs need dose reduction in liver diseases
Adverse effects
 Similar to ACEI except
Less incidence of first dose hypotension
2. Cough , angioedema , dysguesia incidence less
1.
Interactions
 Similar to that with ACEI
T cells and angiotensin II induced
hypertension
 T cells, which express AT1 receptors and NADPH
oxidase, may play an important role in the genesis of A
II–dependent hypertension, particularly obesityrelated hypertension, as the activated T cells are
selectively sequestered in adipose tissue.
 Homing of activated T cells to perivascular fat
promotes vasoconstriction and vascular remodeling.
 Homing of activated T cells to perinephric fat
promotes renal dysfunction and sodium retention
The ARB- MI paradox – a
controversy unresolved
 The major ARB trials in high-risk patients have thus
far demonstrated almost a complete lack of reduction
in MI and mortality despite significant reductions in
blood pressure.
 Paradoxically, rates of MI in some trials have actually
increased with ARBs, which suggests that ARBs and
ACEIs may exert distinctive effects on both the
coronary circulation and atherosclerotic plaque
stability
 This unexpected relationship of ARBs with MI may be
aptly described as the “ARB-MI paradox.”
Martin H. Strauss and Alistair S. Hall: Angiotensin Receptor Blockers May Increase Risk of Myocardial
Infarction : Unraveling the ARB-MI paradox ; Circulation. 2006;114:838-854;
LIONEL H. OPIE and BERNARD J GERSH : DRUGS FOR THE HEART ; 7 Edition 2009
Role of aldosterone in CV disease
 Direct correlation of aldosterone levels and mortality
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in heart failure
Increase in myocardial fibrosis
Inhibition of the release of NO
Increased incidence of arrhythmias
Increased response to vasoconstrictor doses of
angiotensin I
Critical mediator of early angiotensin II induced
experimental myocardial injury
Deleterious effects of aldosterone
Aldosterone antagonists
 Spironolactone
 Eplerenone
 Canrenone ( available only in europe)
What do they do?
 Decrease extracellular markers of fibrosis
 Decreases the release of cardiac norepinephrine
 Vasodilator effects
Spironolactone- mechanism of
action
 It is a steroid chemically related to aldosterone
 Competitive inhibition of the mineralocorticoid
receptor from the interstitial side of the tubular cell
 Inhibits formation of (Aldosterone induced proteins)
AIPs
Spironolactone
 Spironolactone acts as an antagonist and/or agonist at
the following sites:
 Antagonism
Mineralocorticoid receptor
Androgen receptor
 Agonism
Progesterone receptor
Glucocorticoid receptor
Spironolactone bodies
 Long-term administration of
spironolactone gives the
histologic characteristic of
spironolactone bodies in the
adrenal cortex. Spironolactone
bodies are eosinophilic, round,
concentrically laminated
cytoplasmic inclusions
surrounded by clear halos in
preparations stained with
hematoxylin and eosin
Contraindications
 Hyperkalemic states
 Pregnancy - high risk of feminisation of female
fetuses
Pharmacokinetics
 75% oral bioavailability
 Highly bound to plasma proteins
 Completely metabolised in the liver
 Active metabolite canrenone ( ½ - 2/3rd of action in
vivo is due to this metabolite)
 Half life of spironolactone is 1-2 hours; canrenone is 18
hours
Indications
 Hypertension
 To improve survival of stable patients with LV
systolic dysfunction ( EF </= 40% )
 Clinical evidence of CHF after AMI
 Refractory edema in cirrhosis and renal disease – helps
to breakdown resistance to thiazide diuretics due to
secondary hyperaldosteronism
 To counteract K+ loss due to thiazide and loop
diuretics
Interactions
 Dangerous hyperkalemia can occur if given with K+
supplements or drugs causing hyperkalemia ( ACEI or
ARBs)
 Aspirin blocks action of spironolactone by inhibiting
tubular secretion of canrenone
 Spironolactone increases plasma digoxin
concentration
Adverse effects
 Drowsiness , confusion and abdominal discomfort
 Hirsutism,gynecomastia,impotence and menstrual
irregularities
 Hyperkalemia especially in renal disease
 Risk of acidosis in cirrhotics
Eplerenone
 More selective aldosterone antagonist
 Less likely to cause hormonal disturbances like
gynecomastia,impotence and menstrual irregularities
EPLERENONE
 Starting dose 25 mg daily increased to 50 mg daily if
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serum potassium < 5.0 mEq/L
If serum K+ is > 5.5 mEq/L then the dose must be
decreased or discontinued
Specific warning in T2DM with hypertension and
microalbuminuria because of the risk of hyperkalemia
Dose for hypertension ; 50-100 mg once daily
Equally effective in white and black patients.
Trial data – aldosterone
antagonists
 Aldosterone antagonists (or mineralocorticoid receptor
antagonists [MRAs]) are guideline-recommended
therapy for patients with moderate to severe heart
failure (HF) symptoms and reduced left ventricular
ejection fraction (LVEF), and in postmyocardial
infarction patients with HF.
Trial data
 RALES,TOPCAT ( spironolactone)
 EPHESUS ; EMPHASIS-HF ; 4E ( eplerenone)
 AREA IN CHF ( canrenone )
The Eplerenone in Mild Patients Hospitalization and
Survival Study in Heart Failure (EMPHASIS-HF)
 Eplerenone reduced the risk of the primary endpoint of
cardiovascular death or HF hospitalization (hazard ratio
[HR] 0.63, 95% confidence interval [CI] 0.54-0.74, P < .001)
and all-cause mortality (adjusted HR 0.76, 95% CI 0.620.93, P < .008) after a median of 21 months
 The Randomized Aldactone Evaluation Study(RALES)
Eplerenone Post-Acute Myocardial Infarction Heart
Failure Efficacy and Survival Study (EPHESUS)
established that spironolactone and eplerenone,
respectively, increased survival in patients with severe
CHF symptoms from LV systolic dysfunction occurring
with minimal exertion or at rest (New York Heart
Association [NYHA] class III or IV) or CHF after an
acute myocardial infarction
THE 4E STUDY
 The 4E Study (Eplerenone,Enalapril, and
Eplerenone/Enalapril Combination Therapy in Patients
with Left Ventricular Hypertrophy) compared the effects
of 9-month treatment with eplerenone 200 mg/d (n=64),
enalapril 40 mg/d (n=71), or eplerenone 200 mg/d plus
enalapril 10 mg/d (n= 67) on LV mass, systolic and
diastolic blood pressures, and urinary albumin-creatinine
ratio (UACR) in patients with mild-to-moderate
hypertension and echocardiographic evidence of LVH.
 Combination therapy with eplerenone and enalapril
significantly reduced LV mass
Ongoing trial
 TOPCAT study (Treatment of Preserved Cardiac
Function Heart Failure With an Aldosterone
Antagonist)- is ongoing
 At this time, however, there are insufficient clinical
data to recommend the use of aldosterone antagonist
therapy for the treatment of diastolic dysfunction.
Anti-remodelling effect of canrenone in patients
with mild chronic heart failure
(AREA IN-CHF study):
 To test whether canrenone, an aldosterone receptor
antagonist, improves left ventricular (LV) remodelling
in NYHA class II heart failure (HF). Aldosterone
receptor antagonists improve outcome in severe HF,
but no information is available in NYHA class II.
 Canrenone on top of optimal treatment for HF did not
have additional effects on LVEDV, but it increased EF,
and reduced left atrial size and circulating BNP, with
potential beneficial effects on outcome
DRI- Historical aspects
 The concept of blocking the RAAS at its origin by
inhibiting renin has existed for at least 50 years.
 The first synthetic renin inhibitor was pepstatin,
which was followed by first-generation agents that
were active but required parenteral administration
 Oral agents that were subsequently developed, such as
enalkiren,remikiren, and zankiren, had limited
clinical use because they demonstrated poor
bioavailability (< 2%), short half-lives, and weak
antihypertensive activity
Aliskiren
 Aliskiren is the first synthetic non peptide direct renin
inhibitor (DRI) to be approved by the U.S. Food and
Drug Administration and the European Medicines
Agency for treating hypertension in 2007.
 Aliskiren binds to the active site (S1/S3 hydrophobic
binding pocket) of renin, preventing the conversion of
angiotensinogen to angiotensin I
Aliskiren Binding to Renin
Renin
Aliskiren bound to
Active site
Wood et al. BBRC 2003.
ALISKIREN named after ALICE
HUXLEY
Aliskiren - pharmacokinetics
 Direct renin inhibitor
 50 – 80 % decrease plasma renin activity
 Pharmacokinetics
 Accumulation Half-life of ~ 24 hours
 Oral bioavailability of 2.6%
 7 – 8 days to achieve steady state levels
 Elimination Half-life of ~ 48 hours
 25 % excreted by kidneys
 Metabolized by CYP 450-3A4
 Does not induce or suppress CYP 450
 No effect on QT interval
Aliskiren – pharmacokinetics
 Pathway of elimination for aliskiren is via biliary excretion
as unmetabolized drug.
 Less than 1% of an orally administered dose is excreted in
urine.
 Not metabolized by, and does not induce or inhibit,
cytochrome P450 enzymes and shows no clinically relevant
pharmacokinetic interactions with warfarin, lovastatin,
atenolol,celecoxib,cimetidine,amlodipine,valsartan,hydroc
hlorothiazide (HCTZ), or ramipril.
 The pharmacokinetics of aliskiren remain unaffected by
ethnicity, age, gender, hepatic impairment, renal
impairment, and diabetes.
Drug interactions
 It reduces furosemide blood concentration.
 Atorvastatin may increase blood concentration, but no dose
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adjustment is needed.
Due to possible interaction with ciclosporin, the concomitant
use of ciclosporin and aliskiren is contraindicated.
Aliskiren is a minor substrate of CYP3A4 and, more important,
P-glycoprotein
Caution should be exercised when aliskiren is administered with
ketoconazole or other moderate P-gp inhibitors (itraconazole,
clarithromycin, telithromycin, erythromycin, or amiodarone).
Doctors should stop prescribing aliskiren-containing medicines
to patients with diabetes (type 1 or type 2) or with moderate to
severe kidney impairment who are also taking an ACE inhibitor
or ARB, and should consider alternative antihypertensive
treatment as necessary
Adverse effects
 Angioedema
 Hyperkalemia (particularly when used with ACE inhibitors
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in diabetic patients)
Hypotension (particularly in volume-depleted patients)
Diarrhea and other GI symptoms
Headache, Dizziness
Cough
Rash
Elevated uric acid, gout, and renal stones
Potential therapeutic roles of
aliskiren
 Monotherapy for hypertension
 Component of combination therapy for hypertension, with
a diuretic, a CCB, an ACEI, and/or an ARB
 Alternative to ACEIs or ARBs in the management of
hypertension and the prevention of organ damage
 Alternative to ACEIs in patients with diabetic nephropathy
or cardiovascular disease
 Use in patients with diabetic nephropathy or in African
American hypertensive patients, in whom intrarenal
angiotensin II formation occurs via ACE or non–ACEdependent pathways
ali
ATMOSPHERE (Efficacy and Safety of Aliskiren and
Aliskiren/Enalapril Combination on Morbi-mortality in
Patients With Chronic Heart Failure) study
 Aliskiren is currently being evaluated in a phase III
study that will evaluate the efficacy and safety of both
aliskiren monotherapy and aliskiren-enalapril
combination therapy as compared with enalapril
monotherapy in regard to cardiovascular death and
heart failure hospitalizations in NYHA Classes II to IV
HF patients
Role of aldosterone in CV disease
 Direct correlation of aldosterone levels and mortality





in heart failure
Increase in myocardial fibrosis
Inhibition of the release of NO
Increased incidence of arrhythmias
Increased response to vasoconstrictor doses of
angiotensin I
Critical mediator of early angiotensin II induced
experimental myocardial injury
Deleterious effects of aldosterone
Major outcome trials of RAAS
inhibitors with favourable evidence
Trials in post MI HF
 ACEI – SAVE (Captopril), AIRE (Ramipril ), TRACE
(Trandolapril)
 ARB – VALIANT (Valsartan )
 Aldosterone antagonists ( EPHESUS)
Major outcome trials of RAAS
inhibitors with favourable evidence
 Trial in AMI – Early phase
GISSI – lisinopril.
 Trials in cardiovascular risk prevention
ACEI : EUROPA (perindopril), HOPE( ramipril),
PEACE( trandolapril)
ARBs : ONTARGET ( Telmisartan)
Biased AT1 receptor blockade
 A very novel development in the field of ARBs is the
concept of “biased” AT1-receptor blockade.
 Biased ARBs block AT1-receptor-coupled G-protein
signalling in the “traditional” way, while simultaneously
stimulating β-arrestin-coupled signalling which, for
example, results in improved cardiac function.
 TRV120027 is the first biased ARB in clinical development
and is currently being evaluated in a phase II clinical study
for the treatment of heart failure.
AT1-receptor blockade combined with
neutral endopeptidase inhibition
 NEP is responsible for the degradation of atrial and brain
natriuretic factor, which both have cardioprotective
properties. Consequently, inhibition of NEP increases
plasma levels of these protective molecules.
 LCZ696, which may become the first in class ARNI (AT1receptor and NEP inhibitor) lowered blood-pressure more
effectively than valsartan monotherapy in a phase II clinical
trial.
 Phase III clinical trials are currently ongoing to test
LCZ696 for the treatment of heart failure.
 Outcomes of these studies and data about long-term safety
(potential risks for obesity, Alzheimer’s disease and
angioedema have been discussed) have to be awaited
Novel therapies
 AT1-receptor blockade combined with
endothelin A receptor blockade
RE-021 is a dual AT1-receptor and endothelin-A
receptor (ETA) antagonist which was successfully
taken through a phase IIb study in patients in
hypertension . It has potential for use in FSGS
 AT1-receptor blockade combined with nitric oxide
(NO) release is in the pipeline
Novel therapies
 AT2 RECEPTOR AGONISTS
potential use in post-myocardial infarction (MI) cardiac
function,hypertension-induced vascular remodelling,
pulmonary hypertension), neurological (e.g. stroke, spinal
cord injury, Alzheimer’s disease) and immunological (e.g.
multiple sclerosis, rheumatoid arthritis) diseases
 AT2 RECEPTOR ANTAGONISTS in post herpetic pain
 ANGIOTENSIN 1-7 analogues and special formulations
in hypertension, post-MI cardiac failure, metabolic
syndrome, diabetes, renal disease and RA
 Recombinant ACE2 and ACE2 formulations