Newer Antihypertensive Drugs
BushraAbdul Hadi
Philadelphia University
Hypertension: A Significant CV and
Renal Disease Risk Factor
CAD
CHF
LVH
Stroke
Hypertension
 Morbidity
Renal disease
 Disability
Peripheral vascular
disease
National High Blood Pressure Education Program Working Group. Arch Intern Med. 1993;153:186208.
“Older generation drugs used to bring down the
B.P. fairly well at reasonable cost.”
Then, Why do we need new drugs ?
• Observational and limited controlled trials
then showed marginal benefits of BP lowering
for CVAs and IHD
• Unfriendly dosing schedule
• Unpleasant side effects
Vasculopathy continuum
CAD
Risk Factors
CKD
CHF
CVA
PAD
Endothelial Dysfunction
HTN
Metabolic syndrome
Na+ Handling
Sympathetic N system
RAAS
Hypertension
Genetics
Environment
Psycho-social
HTN : Old and New
•
•
•
•
Diuretics
Reserpine
Guanethidine
Alpha Methyl Dopa
ACE Inhibitors
Angiotensin Receptor
Blockers
Beta Blockers
Central Alpha Agon.
Calcium Channel Blockers
Diuretics
Direct Vasodilators
Aldosterone Anta.
NEP Blockers
Potential Pathogenic Properties
of Angiotensin II
 Heart
– Myocardial hypertrophy
– Interstitial fibrosis
 Coronary Arteries
– Endothelial dysfunction with decreased release of nitric oxide
– Coronary constriction via release of norepinephrine
– Formation of oxygen-derived free radicals via NADH
(nicotinamide adenine dinucleotide) oxidase
– Promotion of inflammatory response and plaque instability
– Promotion of low-density lipoprotein cholesterol uptake
Adapted from Opie and Gersh. Drugs for the Heart, 2001.
Potential Pathogenic Properties
of Angiotensin II (continued)

Kidneys
–
–
–
–
–

Increased intraglomerular pressure
Increased protein leak
Glomerular growth and fibrosis
Increased sodium reabsorption
Decreased renal blood flow
Adrenal Glands
– Increased formation of aldosterone

Coagulation System
– Increased fibrinogen
– Increased PAI-1 (plasminogen activator inhibitor-1) relative to
tissue plasminogen factor
Adapted from Opie and Gersh. Drugs for the Heart, 2001.
The Renin-Angiotensin-Aldosterone (RAA) System
Kidneys
Liver secretes
secrete
angiotensinogen renin
Blood
Adrenal cortex
secretes
aldosterone
Renin
Angiotensinogen
Growth
factor
stimulation
Angiotensin
converting
enzyme
(ACE)
Angiotensin I
Sympathetic
activation
Angiotensin II
Vascular
smooth muscle
constriction
Aldosterone
NA+ retention
H2O retention
K+ excretion
Mg+ excretion
RAA System Pathways
to Target Receptor Sites
Na+
Angiotensinogen
K+
Aldosterone
Adrenal
Renin
Other
Chymase
Angiotensin I
CE
Bradykinin
Vascular
Angiotensin II
Inactive
Myocardial
Renal
CNS
ACTH
LIFE: Primary and
Select Secondary Outcomes
Adjusted*
Losartan
Atenolol
(n=4,605) (n=4,588) RR (%) p-value
Primary composite†
508
588
-13
.021
CV mortality
204
234
-11
.21
Stroke
232
309
-25
.001
MI
198
188
+7
.49
383
431
-10
.13
Total mortality
* For degree of LVH and Framingham risk score at randomization
† Number
of onset
patientsDM
with
event
‡ a first primary
New
241
319
-25 <.001
‡ In patients without diabetes at randomization (losartan, n=4,019; atenolol,
Adapted
from B Dahlöf et al. Lancet. 2002;359:995-1003.
n=3,979)
HOPE: Risk Reduction of CV Events
Associated with ACEI (RAS Inhibition)
Treatment
0
MI, Stroke,
CV Death
(primary
end point)
CV Death
MI
Stroke
All-cause
Death
Risk Reduction (%)
-5
-10
-15
-20
-25
-30
-35
-22
(P<.001)
-16
(P=.005)
-20
(P<.001)
-26
(P<.001)
-32
(P<.001)
Adapted from The Heart Outcomes Prevention Evaluation Study Investigators. Effects of an angiotensinconverting enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med.
2000;342:145-153.
Mechanism of Action of
Angiotensin II Receptor Antagonists
Angiotensinogen
Bradykinin
ACE
inhibitors
Alternate
pathways
Angiotensin I
Angiotensin II
Inactive
peptides
AIIRAs
?
AT1 receptor
?
Vasodilation
Attenuate growth and
disease progression
Val-HeFT
Results
• Overall mortality was similar in the two groups
• 13% RRR (p=.009) in combined end point
• Predominantly because of a 27% decrease in
hospitalization for HF in the valsartan group
• Subgroup analyses:
– Valsartan had a favorable effect in patients
receiving neither an ACE inhibitor nor a betablocker
– Valsartan had a favorable effect in patients
receiving an ACE inhibitor or a beta blocker
– Valsartan demonstrated a statistically nonsignificant trend towards an adverse outcome in
ADA Guidelines on Management of
Diabetic Nephropathy
 Hypertensive Type 2 Diabetic Patients*
ARBs are the initial agents of choice
 Type 1 Diabetics with or without
hypertension*

ACEIs are the initial agents of choice
 If one class is not tolerated the other
should be substituted

* With microalbuminuria and clinical proteinuria.
Adapted from American Diabetes Association. Diabetes Care. 2002;25:S85-S89.
Progression to Death, Dialysis,
or Transplant (%)
Effect of ACE Inhibition on
Nephropathy in Type 1
Diabetes
40
30
Placebo
20
*
10
0
0
1
2
Follow-up (y)
* P=.006 vs placebo.
Adapted from Lewis EJ et al. N Engl J Med. 1993;329:1456-1462.
3
4
Captopril
ACE Inhibitors and ARBs
•
•
•
•
•
•
Captopril
Enanlapril
Lisinopril
Ramipril
Perindopril
Quinapril
Losartan
Irbesartan
Candesartan
Valsartan
Telmisartan
Olmesartan
Aliskiren
Proven role of Beta Blockers in
Various Indications
- Hypertension
- Diabetes Mellitus
- CHF
- CAD
Effect of Beta-Blockers on
mortality following myocardial infarction
23
No diabetes mellitus, all
Diabetes mellitus, all
20
17
15
10
13
10
10
7
5
0
No diabetes mellitus,
no beta-blocker
No diabetes mellitus,
beta-blocker
Diabetes mellitus,
no beta-blocker
Diabetes mellitus,
beta-blocker
Kjekshus J et al. Eur Heart J 1990; 11: 43-50
1 year-mortality (%)
25
Survival rate
1.00
0.95
0.90
0.85
0.80
With ß-blockers
Without ß-blockers
P= 0.0001
0.75
1
2 Year 3
4
5
Jonas et al. Am J Cardiol 1996; 77: 1273 et seqq.
Usefulness of beta-blocker therapy in patients
With Diabetes Mellitus and CAD (BIP)
Effect of Beta-Blockers on
Mortality in Heart Failure Patients
Trial End Point
Risk Reduction, % (95% CI)
US Carvedilol
Combined end point:
risk of hospitalization
or death
38% lower risk (18%-53%)
P< 0.001
CIBIS-II (bisoprolol)
All-cause mortality
34% lower risk
P< 0.0001
MERIT-HF (metoprolol)
All-cause mortality
34% lower risk (0.53–
0.81)
P=0.0062 after adjusted
interim analysis
BEST (bucindolol)
All-cause mortality
8.5% lower risk
P=NS
COPERNICUS (carvedilol)
All-cause mortality
35% lower risk*
Clinical Trial
*Preliminary data from XXII Congress of the European Society of Cardiology
Effects of Metoprolol CR and Placebo on Neurohormonal Activation
Placebo
250
225
225
200
175
182
200
165
175
150
128
125
105
150
125
100
100
75
75
50
Metoprolol
250
35.9 38.9
50
25
25
0
0
Plasma
Angiotensin Aldosterone
renin ng/ml II pg/ml
pg/ml
Baseline
24 weeks
The Resolvd Investigators. 1999.
NS
*
147
129
113
99
*
34.3 30.9
Plasma
Angiotensin Aldosterone
renin ng/ml II pg/ml
pg/ml
Baseline
24 weeks
*P<0.05
NS: Non Significant
Effect of -Blocker in Heart Failure
Mega-trials on: metoprolol, bisoprolol, carvedilol &
bucindolol.
Consistent good results in mild / moderate HF.
Significant ↓ in rate of hospitalisation.
Fair improvements in symptoms & QOL.
Improvements in hemodynamics of HF & remodeling.
Results in severe HF are not uniform.
Bucindolol in BEST showed no benefits.
Sub-analysis of CIBIS-II (Bisoprolol) & MERIT-HF: ↓ benefits
in more severe HF.
COPERNICUS: significant benefits in severe HF.
Lipophilic beta
blockers are an ideal
choice in patients at
high risk of SCD,
prior MI, HT,CHF
Beta Blockers
•
•
•
•
•
Propranolol
Atenolol
Metoprolol( Sustained Release)
Bisoprolol
Carvedilol
ALLHAT
Diuretics
Because of the superiority of thiazide-type
diuretics in preventing one or more major
forms of CVD and their lower cost, they
should be the drugs of choice for first-step
antihypertensive drug therapy.
Hydrochlorthiazide
Metolazone
Furosemide
Torsemide
Amiloride
Calcium Channel Blockers
Very effective in lowering BP
 Safe
 OD or BID Dose
 No significant outcome benefits
 Peripheral edema

Nifedipine(Long Acting)
Amlodepine
Verapamil
Nicardepine
Lercanidipine
Felodepine
Miscellaneous
• Direct Vasodilators
– Dihydrallazine
– Minoxidil
– Prazosin
• Central Alpha Agonists
– Clonidine
– Moxolidine
• Aldosterone antagonists
– Spironolactone
– Eplerenone
• Indapamide
Benefits of Lowering BP
Average Percent Reduction
Stroke incidence
35–40%
Myocardial infarction
20–25%
Heart failure
50%
U.S. Department of
Health and Human
Services
National Institutes
of Health
National Heart, Lung,
and Blood Institute
National Heart, Lung, and Blood
Institute
National High Blood Pressure
Education Program
The Seventh Report of the
Joint National Committee
on
Prevention, Detection,
Evaluation, and Treatment
of High Blood Pressure
(JNC 7)
Blood Pressure
Classification
BP Classification
Normal
SBP mmHg
<120
DBP mmHg
and
<80
Prehypertension
120–139
or
80–89
Stage 1
Hypertension
Stage 2
Hypertension
140–159
or
90–99
>160
or
>100
Compelling Indications for
Individual Drug Classes
Compelling
Indication
Initial Therapy
Clinical Trial Basis
Heart failure
THIAZ, BB, ACEI,
ARB, ALDO ANT
ACC/AHA Heart Failure
Guideline, MERIT-HF,
COPERNICUS, CIBIS,
SOLVD, AIRE, TRACE,
ValHEFT, RALES
BB, ACEI, ALDO
ANT
ACC/AHA Post-MI
Guideline, BHAT,
SAVE, Capricorn,
EPHESUS
THIAZ, BB, ACE,
CCB
ALLHAT, HOPE,
ANBP2, LIFE,
CONVINCE
Postmyocardial
infarction
High CAD risk
Compelling Indications for
Individual Drug Classes
Compelling
Indication
Initial Therapy
Clinical Trial Basis
Options
THIAZ, BB, ACE, ARB, NKF-ADA
Diabetes
Guideline, UKPDS,
CCB
ALLHAT
Chronic kidney
ACEI, ARB
NKF Guideline,
disease
Captopril Trial,
RENAAL, IDNT,
REIN, AASK
Recurrent stroke THIAZ, ACEI
PROGRESS
prevention
Cardiovascular Diseases
• Cerebrovascular disease
–Indication for treatment, except immediately
after ischemic cerebral infarction.
• Coronary artery disease
–Benefits of therapy well established.
• Left ventricular hypertrophy
–Antihypertensive agents (except direct
vasodilators) indicated.
–Reduced weight and decreased sodium
intake beneficial.
Cardiovascular
Diseases (continued)
• Cardiac failure
–ACE inhibitors, especially with digoxin or
diuretics, shown to prevent subsequent
heart failure.
• Peripheral arterial disease
–Limited or no data available.
New Features and Key Messages
 For persons over age 50, SBP is a more important
than DBP as CVD risk factor
 Starting at 115/75 mmHg, CVD risk doubles with
each increment of 20/10 mmHg throughout the BP
range.
 Persons who are normotensive at age 55 have a
90% lifetime risk for developing HTN.
 Those with SBP 120–139 mmHg or DBP 80–89
mmHg should be considered prehypertensive who
require health-promoting lifestyle modifications to
prevent CVD.
JNC-VII New Features and
Key Messages (Continued)
Thiazide-type diuretics should be initial
drug therapy for most, either alone or
combined with other drug classes.
 Certain high-risk conditions are compelling
indications for other drug classes.
 Most patients will require two or more
antihypertensive drugs to achieve goal BP.
If BP is >20/10 mmHg above goal, initiate
therapy with two agents, one usually
should be a thiazide-type diuretic.
Preventable CHD Events from Control
of Hypertension in US Adults
(Wong et al., Am Heart J 2003; 145: 888-95) (cont.)
• The greatest impact (absolute numbers)
from control of hypertension occurs in
men, older persons, and those with
isolated systolic hypertension
• The greatest proportion of preventable
CHD events from control of hypertension
occurs in women
• Optimal control of blood pressure could
prevent more than one third of CHD events
in men and more than half of CHD events
in women
Evolution of
Antihypertensive Therapies
Effectiveness
Tolerability
1940’s
1950
1960’s
1957
-blockers
Direct
vasodilators
Peripheral
sympatholytics
Ganglion
blockers
Veratrum
alkaloids
1970’s
1980’s
ARBs
ACE
inhibitors
Thiazides
diuretics
Central 2
agonists
Calcium
antagonistsnon DHPs
blockers
1990’s
Calcium
antagonistsDHPs
2001
VPIs
Others
We are still evolving towards finding an
Ideal Antihypertensive
Preventable CHD Events from
Control of Hypertension in US
Adults
(Wong et al., Am Heart J 2003; 145: 888-95)
56
60
PAR% / NNT
50
39
37
40
31
30
20
21
21
19
11
10
0
Men PAR%
Women PAR%
Treatment to <140/90 mmHg
Men
NNT
Women NNT
Treatment to <120/80 mmHg
PAR% = population attributable risk (proportion of CHD events preventable),
NNT = number needed to treat to prevent 1 CHD event ; <0.01 comparing
Compelling Indications for
Certain Drug Classes
HTN with CAD


Beta blockers: cardioprotective
(reinfarction, arrhythmias and sudden
death)
ACE inhibitors: MI with systolic
dysfunction- heart failure and mortality
improved



Aliskiren is a novel, completely nonpeptide, orally active renin
inhibitor that blocks the first and rate-limiting step of the reninangiotensin system
Alagebrium, an advanced glycation end product (AGE)
crosslink breaker, has been shown to reduce SBP in patients
with uncontrolled systolic hypertension,
progestin drospirenone and 17beta-estradiol (DRSP/E2),
developed for postmenopausal hormone replacement therapy,
has been shown to lower both clinic and ambulatory SBP in
postmenopausal women
Pathophysiology of Heart Failure
Cardiac injury
Increased load
Activation of RAA System, SNS, and cytokines
Reduced systemic perfusion
Altered
gene
expression
Growth and
remodeling
Ischemia and
energy
depletion
Apoptosis
Necrosis
Cell death
Adapted from: Eichhorn EJ, Bristow MR. Circulation. 1996;94:2285-2296.
Direct
toxicity
Pathogenesis of HT
Reasons are
mulitfactorial..
Vasoconstriction
Renin
Angiotensin II
Angiotensin I
Increased Na+ & water reabsorption
Summary