Download Newer Antihypertensive Drugs

Newer Antihypertensive Drugs
Vinod Sharma
National Heart Institute
New Delhi
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Newer Antihypertensive Drugs
Arterial Hypertension, a widespread but controllable
disease affecting as much as 30-45% of general
population.
Despite the Broad spectrum of already available
pharmacological (as well as non-pharmacological) means
of BP control, there is no evidence for a change in
average blood pressure value over the past decade.
Eur Heart J 2013
Rate of stroke (as an indirect indicator of blood pressure
levels in population) tends to increase in Eastern
European Countries & Central Asia.
-
Obvious medical demand for novel approach / drugs
to treat high blood pressure.
Eur Heart J 2011 2
Newer Antihypertensive Drugs
Current “Gold Standard” Therapy
 ACE Inhibitors
 16 ACE Inhibitors
CAPP
Imidapril
STOP – 2
Cilazapril
HOPE
 AT1R Blockers
LIFE
 7 AT1R Blockers
Azilsartan
VALUE
ONTARGET
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Newer Antihypertensive Drugs
AZILSARTAN
More potent than most of the clinically available
ARBs for inhibiting binding of Angiotensin II to
human AT1 Receptor membrane preparation.
Dissociates from AT1 Receptor much more slowly
than other ARBs.
Reduce 24 hrs BP in hypertensive humans without
serious co-morbidities more effectively than
maximum approved doses of Olmesartan, Valsartan
& Candesartan.
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Effects of the Angiotensin Receptor
Blocker Azilsartan Medoxomil Versus
Olmesartan & Valsartan on Ambulatory
and Clinic Blood Pressure in Patients
with Stages 1 and 2 Hypertension
William B White, Michael A Weber, Domenic Sica, George L Bakris, Alfonso Perez, Charlie Cao,
Stuart Kupfer
Azilsartan Medoxomil at its maximal dose has
superior efficacy to both Olmesartan and Valsartan
at their maximal, approved doses without increasing
adverse events. Azilsartan Medoxomil could provide
higher rates of hypertension control within the ARB
class.
Hypertension 2011; 57: 413-4205
A meta-analysis of randomized
controlled trials of Azilsartan
therapy for blood pressure reduction
Hisato Takagi, Yusuke Mizuno, Masao Niwa, Shin-nosuke Goto and Takuya Umemoto for the
ALICE (All-Literature Investigation of Cardiovascular Evidence) Group
In Conclusion, Azilsartan therapy appears to provide
a greater reduction in BP than control therapy in
patients with hypertension
Hypertension Research (2014), 37, 432-437
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Elevated PRA may be associated with
increased risk of myocardial infarction
For every 2-unit increase in PRA, there was an overall
25% increase in MI incidence
MI rate/1000 person-years
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Plasma renin activity (PRA)
High
Normal
Low
30
20
10
0
High risk:
2 additional
risk factors†
†Risk
Moderate risk:
1 additional
risk factor†
factors defined as: smoking, cholesterol
>6.3 mg/dL, or left ventricular hypertrophy
Alderman et al. Am J Hypertens 1997.
Low risk:
No additional
risk factors†
Elevated PRA predicts cardiac events in
patients receiving optimal HF treatment
PRA and cardiac events (n=699, patients on treatment for heart failure)
1.0
PRA <5.48 nmol/L/h (<7.11 ng/mL/h)
0.8
Cumulative survival
n=517
0.6
p<0.001
PRA >5.48 nmol/L/h (>7.11 ng/mL/h)
n=147
0.4
0.2
0
0
500
1000
Follow-up (days)
Vergaro et al. Eur Heart J 2008;29(Suppl.):393 [Abstract]
1500
2000
2500
3000
Aliskiren 150-300 mg daily –
new generation in antihypertensive treatment
First direct renin inhibitor for hypertension
Uniquely lowers PRA in monotherapy and combination
Effective and sustained monotherapy
Additional BP lowering when combined with other
antihypertensives
Sustained 24-hour BP control with prolonged effect after
withdrawal
Placebo-like safety and tolerability profile
Potential for improved end-organ protection via optimal
suppression of the renin system
– BNP reduction in heart failure
– LVH regression in hypertensive obesity
– Proteinuria reduction in DM nephropathy
“It is said that present is
pregnant with future”
“Voltaire”
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Combined
Vasopeptidase
(NEP & ACE)
inhibition
AT2R
Stimulation
Aldosterone
Synthetase
inhibitors
(P) RR
Receptors
Blockers
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Newer Antihypertensive Drugs
AT2R Agonists: Stimulating the RAAS
AT2R mediates actions opposing AT1R stimulation:
INHIBITION of cell growth & proapoptotic actions
Enhanced NO formation in vascular tissue
Attenuation of myointimal hyperplasia after
endothelial denudation
Reduction of undesired neointimal growth, cardiac
remodeling or proliferative retinopathy.
AT2R stimulation, an exciting & innovative approach to
treat hypertension.
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AT2R Agonist – Stimulating RAAS
Compound 21
A Selective AT2R agonist with oral bioavailability of 20 -30%
Improved SBP / DBP after experimental MI in rats
Anti-inflammatory and anti-apoptotic action, unrelated to BP
changes.
Inhibits Nuclear factor Kappa B leading reduce expression of
inflammatory Cytokins, Interleukins-6 & Tumor necrosis factor.
AT2R
– Beneficial in hypertension
- Long term activation reduce angiogenesis.
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Dual Vasopeptidase Inhibitors
Inhibition of Neprilysin, potentiates:
-
Diuretics
-
Natriuresis
-
Vaso-relaxant effects of endogenous natriuretic
peptide.
Increase concentration of vasoconstrictor peptides
(Angiotensin
2
and
Endothelin-1),
which
are
metabolized by Neprilysin.
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Opposing Physiological Effects of Sole
Neprilysin Inhibition
Neprilysin
Substrate
Plasma levels
Vasodilation
Natriuresis /
Diuresis
Cardiovascular
Remodeling
ANP
BNP
CNP
Angiotensin-II
Endothelin – I
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Synergistic antihypertensive effect of dual NEP-ACE
Inhibitors
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Dual Neprilysin – ACE inhibitor
OMAPATRILAT
-
Highly specific
-
Non peptidergic
-
Orally active dual vasopeptidase inhibitor
-
More
effective
lowering
of
BP
than
ACEI
(Lisinopril & Enalapril)
Frequency of angio-edema high due to accumulation
of Bradykinin, substance P & Neurokinin.
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Vasopeptidase Inhibition: NEP + ACE
OMAPATRILAT
Combined ACE & NEP inhibition might be effective in
the treatment of hypertension & heart failure.
Concern – higher incidence of angio-edema
OVERTURE - (Circulation 2002)
OCTAVE - (Curr Opin Investig Drugs 2001)
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Dual Neprilysin – ACE inhibitor
ILEPARTIL
-
Orally active
-
Prolonged, intense inhibition of ACE compared
to Ramipril
-
Higher inhibition of ACE than of Neprilysin
-
Better tolerated
-
Phase III trial
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Dual Acting ARNI
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Dual Acting Angiotensin Receptor –
Neprilysin inhibitor
Overcome risk of Angio-edema because no effect on
metallopeptidase that participates in bradykinin
breakdown
LCZ 696 (Molecular moiety of Valsartan & Neprilysin
Inhibitor prodrug AH 0377)
Compared with Valsartan (n = 1328)
-
Fully additive reduction of BP
-
No case of Angio-edema in the 8 weeks Rx
period.
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Synergistic antihypertensive effect of dual NEP-ECE
inhibitors
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Dual Neprilysin & Endothelin
Converting Enzyme Inhibitors
(contd)
NEP + ECE INHIBITOR
-
Blocks
pro-inflammatory
and
profibrotic
effects
of
Endothelin 1
-
Enhance Plasma concentration of Natriuretic peptide
-
Overcome limitation of sole Neprilysin inhibition
-
Natriuretic action of Neprilysin can oppose salt & water
retention caused by non-selective blockade of endothelin
receptors
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Dual Neprilysin & Endothelin
Converting Enzyme Inhibitors
(contd)
DAGLUTRIL
-
A potent inhibitor of combined NEP & ECE
inhibitors
-
Phase II clinical development
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Newer Antihypertensive Drugs –
Endothelin Antagonists
Endothelin 1 – A potent vasoconstrictor peptide acts
through Endothelin A & B receptors
Endothelin A receptor Antagonists – Bosentan
Endothelin A + B
– Arosentan
- Enrasentan
- Tozesentan
Endothelin 1 Antagonist – Resistant Hypertension
– Significantly lowered BP compared to Placebo
-
Water
Retention,
transaminases
edema
&
rise
in
liver
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Newer Antihypertensive Drugs –
Endothelin Antagonists
(contd)
DARUSENTAN (Mixed Endothelin A & B Antagonists
– Phase III trial (Gilead Sciences)
More effective than placebo in lowering clinic & ABP,
in addition to Rx with three or more antihypertensive
drugs.
25% patients had fluid retention & edema, managed
by Diuretic.
Weber MA et al: Lancet 2009
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ACE2 / Ang (1-7) / Mas Receptor axis
Agonists
Mas receptors “Protective RAAS”
Mas receptor effects
Antifibrosis
Antiinflammation
Antiproliferation
No release
Non-peptide Mas Receptor Agonist (AVE-0991)
“Besides BP lowering effects, AVE-0991 seems to
exert blood pressure independent renoprotective
effect”
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Newer Antihypertensive Drugs
Aldosterone Receptor Antagonists
Spiranolactone
-
Effective BP reduction
-
Reduce mortality in heart failure
-
Poor selectivity for mineralocorticoid receptor
leading to
progesterone
&
testosterone
–
dependent effects, loss of lipido, menstrual
irregularities, impotence & gynaecomastia
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Newer Antihypertensive Drugs
Selective
mineralocorticoid
receptor
blocker
–
Eplerenone
------------------------------------------------------------------------------Non-inferior to Amlodipine, Enalapril & Losartan in
reducing BP.
Reduce all cause mortality in cases with heart
failure.
Sexual adverse effects are less pronounced with
Eplerenone than with Spironolactone.
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Newer Antihypertensive Drugs
Aldosterone Synthetase Inhibitors
Inhibits the formation of Aldosterone.
FAD 286 / SPP2745
-
Lowered BP in rats
-
Good specificity
-
Offer protection to cardiac, renal & vascular
system
-
Compatible with conventional therapy
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Renalase: a novel target
Renalase, a novel kidney-related peptide that might impact CV
health.
Renalase is the first known circulating amine oxidase in plasma
that metabolizes catecholamines.
Plasmatic activity of renalase is undetectable under basal
conditions, but can be provoked by the release or infusion of
catecholamines.
Renalase is also expressed in the heart, skeletal muscle, and
liver. Kidney seems to be the major source of circulating
renalase because no compensatory rises in reduced renalase
levels are observed among patients with end-stage renal failure
or in nephrectomized rats.
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Renalase: a novel target
(contd)
The down regulation, or knock-out, of renalase is associated
with elevated BP.
Recombinant renalase has been shown to dose-dependently
lower BP, heart rate, and contractility & to protect the
myocardium against ischemia – reperfusion injury
Metabolism of the renal vasodilator, dopamine, by renalase
could raise safety concerns and limit its therapeutic potential.
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Novel Drugs in Preclinical Development
Nitric Oxide Donors
-
Nitrosyl – Cobinamide
-
Nitric Oxide releasing Pharmacodynamic hybrids of Losartan &
Telmisartan
-
Naproxcinod
Orally active Aminopeptidase – A Inhibitors (QGC001)
-
Targets
aminopeptidase
A,
the
enzyme
that
generates
angiotensin – 3 in the brain, a major effector peptides of Brain
Renin – Angiotensin system in control of Arginine – vasopressin
release & blood pressure
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Newer Antihypertensive Drugs
INNOVATIVE TARGETING OF ANGIOTENSIN II
ANTI-RAAS VACCINATION
1960, Early anti-renin formula was associated with
severe autoimmune kidney disease
2000, Immunization against Angiotensin
Angiotensin I vaccine (PMD 3117)
-
Some evidence of RAAS Blockade
-
Failed to lower BP
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Newer Antihypertensive Drugs
(contd)
ANTI-RAAS VACCINATION
Anti-Angiotensin II Antigenic peptide conjugated to a
virus like particle (CYT006)
-
Lowered SBP by up to 21 mm Hg in rats
-
Well tolerated in phase I study
-
Modest BP reduction 9/4 mm Hg in a Phase IIa
study.
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Antihypertensive Vaccine
Better patient compliance
Reported ability of CYT006 to reduce BP
throughout the whole day and blunt early
morning surge.
Inadequate BP reduction
Safety concern
Needs further study
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Human Vaccines & Immunotherapeutics, March 2014
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