Newer Antihypertensive Drugs

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Newer Antihypertensive Drugs

• BushraAbdul Hadi
• Philadelphia University

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Hypertension A Significant CV and Renal Disease
Risk Factor
CAD
CHF LVH
Stroke
Hypertension
? Morbidity ? Disability
Renal disease
Peripheral vascular disease
National High Blood Pressure Education Program
Working Group. Arch Intern Med. 1993153186-208.
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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

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Vasculopathy continuum
CAD CHF CVA
PAD
Risk Factors Endothelial Dysfunction

CKD HTN
Metabolic syndrome
5
Na Handling Sympathetic N system
RAAS
Hypertension
Genetics Environment
Psycho-social
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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
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Potential Pathogenic Propertiesof 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.
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Potential Pathogenic Propertiesof 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.
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The Renin-Angiotensin-Aldosterone (RAA) System
Kidneys secreterenin
Adrenal cortex secretes aldosterone
Liver secretes angiotensinogen
Angiotensinconvertingenzyme(ACE)
Blood
Renin
Angiotensinogen
Aldosterone
Angiotensin II
Angiotensin I
NA retention H2O retention K excretion Mg
excretion
Growthfactor stimulation
Vascular smooth muscle constriction
Sympathetic activation
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RAA System Pathways to Target Receptor Sites
Na
K
Angiotensinogen
Aldosterone
Adrenal Vascular Myocardial Renal CNS
Renin
Other
ACTH
Chymase
CE
Angiotensin I
Angiotensin II
Bradykinin
Inactive
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LIFE Primary and Select Secondary Outcomes
Losartan Atenolol (n4,605) (n4,588)
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 Total mortality 383 431 -10
.13 New onset DM 241 319 -25 lt.001
Adjusted
For degree of LVH and Framingham risk score at
randomization Number of patients with a first
primary event In patients without diabetes at
randomization (losartan, n4,019 atenolol,
n3,979)
Adapted from B Dahlöf et al. Lancet.
2002359995-1003.
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HOPE Risk Reduction of CV EventsAssociated with
ACEI (RAS Inhibition) Treatment
Adapted from The Heart Outcomes Prevention
Evaluation Study Investigators. Effects of an
angiotensin-converting enzyme inhibitor,
ramipril, on cardiovascular events in high-risk
patients. N Engl J Med. 2000342145-153.
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Mechanism of Action ofAngiotensin II Receptor
Antagonists
Angiotensinogen
Alternate pathways
Bradykinin
Angiotensin I
ACE inhibitors
Angiotensin II
Inactive peptides
AIIRAs
?
AT1 receptor
Other AT receptors
AT2 receptor
Vasodilation Attenuate growth and disease
progression
?
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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
  beta-blocker
• Valsartan had a favorable effect in patients
  receiving an ACE inhibitor or a beta blocker
• Valsartan demonstrated a statistically
  non-significant trend towards an adverse outcome
  in patients receiving an ACE inhibitor and a beta
  blocker

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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. 200225S85-S89.
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Effect of ACE Inhibition on Nephropathy in Type 1
Diabetes
Placebo
Progression to Death, Dialysis, or Transplant ()

Captopril
Follow-up (y)
P.006 vs placebo. Adapted from Lewis EJ et
al. N Engl J Med. 19933291456-1462.
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ACE Inhibitors and ARBs

• Captopril
• Enanlapril
• Lisinopril
• Ramipril
• Perindopril
• Quinapril

Losartan Irbesartan Candesartan Valsartan Telmisar
tan Olmesartan Aliskiren
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• Proven role of Beta Blockers in Various
  Indications
• - Hypertension
• Diabetes Mellitus
• CHF
• CAD

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Effect of Beta-Blockers on mortality following
myocardial infarction
25
23
No diabetes mellitus, all
Diabetes mellitus, all
20
17
No diabetes mellitus, no beta-blocker
15
13
1 year-mortality ()
No diabetes mellitus, beta-blocker
Kjekshus J et al. Eur Heart J 1990 11 43-50
10
10
10
7
Diabetes mellitus, no beta-blocker
5
Diabetes mellitus, beta-blocker
0
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Usefulness of beta-blocker therapy in patients
With Diabetes Mellitus and CAD (BIP)
1.00
0.95
0.90
Survival rate
Jonas et al. Am J Cardiol 1996 77 1273 et seqq.
With
ß
-blockers
0.85
Without
ß
-blockers
0.80
P
0.0001
0.75
1
2
3
4
5
Year
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Effect of Beta-Blockers on Mortality in Heart
Failure Patients
Preliminary data from XXII Congress of the
European Society of Cardiology
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Effects of Metoprolol CR and Placebo on
Neurohormonal Activation
250 225 200 175 150 125 100 75 50 25 0
Metoprolol
250 225 200 175 150 125 100 75 50 25 0
Placebo
182
NS
165
147
129
128
113
105
99
38.9
34.3
35.9
30.9
The Resolvd Investigators. 1999.
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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.

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Lipophilic beta blockers are an ideal choice in
patients at high risk of SCD, prior MI, HT,CHF
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Beta Blockers

• Propranolol
• Atenolol
• Metoprolol( Sustained Release)
• Bisoprolol
• Carvedilol

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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
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Calcium Channel Blockers

• Very effective in lowering BP
• Safe
• OD or BID Dose
• No significant outcome benefits
• Peripheral edema

Nifedipine(Long Acting) Amlodepine Verapamil Nicar
depine Lercanidipine Felodepine
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Miscellaneous

• Direct Vasodilators
• Dihydrallazine
• Minoxidil
• Prazosin
• Central Alpha Agonists
• Clonidine
• Moxolidine
• Aldosterone antagonists
• Spironolactone
• Eplerenone
• Indapamide

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Benefits of Lowering BP
Average Percent Reduction Stroke incidence
3540 Myocardial infarction 2025
Heart failure 50
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National Heart, Lung, and Blood
InstituteNational High Blood Pressure Education
Program
The Seventh Report of the Joint National
Committee onPrevention, Detection, Evaluation,
and Treatment of High Blood Pressure (JNC 7)
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Blood Pressure Classification
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Compelling Indications for Individual Drug
Classes
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Compelling Indications for Individual Drug
Classes
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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.

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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.

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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 120139 mmHg or DBP 8089 mmHg
  should be considered prehypertensive who require
  health-promoting lifestyle modifications to
  prevent CVD.

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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 gt20/10 mmHg above goal, initiate therapy
  with two agents, one usually should be a
  thiazide-type diuretic.

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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

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Evolution of Antihypertensive Therapies
Effectiveness
Tolerability
1940s 1950 1957 1960s 1970s 1980s 1990s 2001
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We are still evolving towards finding an Ideal
Antihypertensive
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Preventable CHD Events from Control of
Hypertension in US Adults(Wong et al., Am Heart
J 2003 145 888-95)
PAR population attributable risk (proportion
of CHD events preventable), NNT number needed
to treat to prevent 1 CHD event lt0.01
comparing men and women for PAR
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Compelling Indications for Certain Drug Classes
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HTN with CAD

• Beta blockers cardioprotective (reinfarction,
  arrhythmias and sudden death)
• ACE inhibitors MI with systolic dysfunction-
  heart failure and mortality improved

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• Aliskiren is a novel, completely nonpeptide,
  orally active renin inhibitor that blocks the
  first and rate-limiting step of the
  renin-angiotensin 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

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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
Direct toxicity
Apoptosis
Necrosis
Cell death
Adapted from Eichhorn EJ, Bristow MR.
Circulation. 1996942285-2296.
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Pathogenesis of HT

• Reasons are mulitfactorial..

Vasoconstriction
Renin
Angiotensin II Angiotensin I
Increased Na water reabsorption
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Summary