bb in htn 2007
TRANSCRIPT
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In the name of Allah, Most Gracious, Most Merciful
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BETA BLOCKERS-IN HYPERTENSION
- Dr. Mohammed Sadiq Azam
First yr. PG
M - I
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HISTORY
1948: Ahlquist classified adrenergic receptors
into and receptors.
1958: Dichloroisoprenaline (DCI) First BB
1963: Therapeutic breakthrough, Propronololintroduced by J.W.Black
1980: BB become the most popular antiHTNs
after diuretics. Practolol First 1 selective.
2003: BB become the most controversial
antiHTNs!!
2010: ??????
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PHYSIOLOGY OF RECEPTORS
Receptor 1 2 3
Location Heart,
JG cells of kidney
Bronchi, Blood
vessels, Uterus, GIT,
Urinary tract, Eye
Adipose tissue
Selective agonist Dobutamine SalbutamolTerbutaline
BRL37344
Selective antagonist Metoprolol
Atenolol
ISI118551
-methyl propronlol
CGP20712A (+B1)
ICI118551 (+B2)
Potency of NA as
agonist
Strong Weak Strong
Role Cardiac
+ Inotropic
+ Chronotropic
Vasodilatation
Bronchodilatation
Glucagon levels
Lipolysis
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CLASSIFICATION OF BLOCKERS
(Ref: Tripathi KD, antiadrenergic drugs, Essentials of Med. Pharmacology, p124, 5e:2003)
1. Non selective (1 & 2): Without ISA :
Propronolol
Sotalol
Timolol
With ISA:
Pindolol
With additional blocking property:
Labetolol
Carvedilol
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CLASSIFICATION OF BLOCKERS
(Ref: Tripathi KD, antiadrenergic drugs, Essentials of Med. Pharmacology, p124, 5e:2003)
2. Cardioselective (1):
Metoprolol
Acebutolol
Esmolol
Atenolol Bisoprolol
Betaxolol
Celiprolol
3. Selective (2): Butoxamine
ICI118551
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CLASSIFICATION OF BLOCKERS
(Ref: Braunwald, Systemic Hypertension:Therapy, Heart Disease, p1002:f38-11,7e:2005)
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CLASSIFICATION OF BLOCKERS
GENERATION CLASS COMPOUND
First Non selective Propronolol
Second Selective Metoprolol
Third Beta blocker - vasodilator Carvedilol
Bucindolol
Nebivolol
(Ref: Braunwald, Drugs in treatment of Heart Failure, Heart Disease, p590:t23-11,7e:2005)
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PHARMACODYNAMICS
On Heart: HR, Force of contraction, Cardiac Output
systole by conduction ( synergy of fibres)
Cardiac work, O2 consumption:
Total coronary flow:
Restricted to subepicardial region, subendocardial region is not affected.
Overall Effect : O2 supply/demand status & exercise tolerance.
Refractory period & automaticity - rate of DP in ectopic foci
AV conduction : Delayed
doses: membrane stabilisation & direct depressant (Quinidine like) effect.
Blocks cardiac stimulatory action of adrenergic drugs but NOT Digoxin, Ca,
Methyl xanthines, glucagon.
(Prototype: Propronlol)
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PHARMACODYNAMICS
On Blood vessels:
Inhibits VD & BP caused by Isoprenaline
Augments BP caused by Adrenaline
Re-reversal of vasomotor reversal seen after -blockade (Reverse Dale)
No direct effect on blood vessels => little acute change in BP
Prolonged use: BP in hypertensive subjects but NOT in normotensives.
(Prototype: Propronlol)
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PHARMACODYNAMICS
Mechanisms of Anti Hypertensive action:
1. Initially: TPR and C.O (15-20%) => little change in BP
Chronic use: resistance vessels adapt TPR , CO => BP
2. NA release from sympathetic terminals due to blockade of-mediated
release.
3. 1 mediated renin release from kidney (upto 60% in BB with ISA - )
4. Central action sympathetic outflow
(Prototype: Propronlol)
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PHARMACOKINETICS
Oral absorption: Good
Low Bioavailability (due to FP metabolism in Liver)
Oral:Parental dose ratio = 40:1
Interindividual variation in extent of FPM +
Lipophilic, easily crosses BBB
Liver metabolism depends on HBF ( on chronic use)
BA with meals as food FPM
Metabolism is saturatable. BA with doses
Plasma protein binding > 90%
Excretion in urine as Glucronides
(Prototype: Propronlol)
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DRUG INTERACTION
Additive depression of SA node and AV conduction with digitalis and
verapamil .
Delayed recovery from hypoglycemia
Unopposed action - TPR
Indomethacin/NSAIDs- Attenuate anti HTN action
Cimitidine inhibits Ppnl metabolism.
Ppnl metabolism by HBF
Ppnl BA of CPZ by FPM
(Prototype: Propronlol)
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ADR & CONTRA INDICATIONS
Fatigue - MC ADR
Myocardial insufficiency C/I in severe HF
Bradycardia - in patients with SSS
variant angina unopposed mediated coronary VC
Impairment of carbohydrate tolerance in pre diabetics.
Altered plasma lipid profile - TGL , LDL - HDL
Sudden withdrawal rebound HTN, angina, sudden death
exercise capacity 2 mediated VD to skeletal muscle
Worsening of PVD
(Prototype: Propronlol)
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ADR & CONTRA INDICATIONS
Non selective BBs can precipitate life threatening AE of BA
C/I in partial/ complete heart block can ppt arrest
C/I in pheochromocytoma can ppt a severe HTN crisis.
Sexual dysfunction in males
?? Effect on depression reported r/o suicide compared to
CCB/ACEI
Caution in DM, elderly, pregnancy (esp. non specific BB)
(Prototype: Propronlol)
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THE MILLION DOLLAR QUESTION
And now
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TO BE OR NOT TO BE??
The Role of Beta Blockers in Hypertension
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WHAT THE JNC 7 SAYS
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WHAT THE JNC 7 SAYS
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WHAT DOES EVIDENCE POINT AT??
EBM
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THE COCHRANE REVIEW
Evidence no.1
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COCHRANE ON BB in HTN
The review, published online January 24, 2007, bases this conclusion on "the
relatively weak effect of beta blockers to reduce stroke and the absence of an effect
on coronary heart disease when compared with placebo or no treatment"
and"the trend toward worse outcomes in comparison with calcium-channel blockers,
renin-angiotensin-system inhibitors, and thiazide diuretics.
Most of the evidence for these conclusions comes from trials where atenolol was
the beta blocker used, and it is not known at present whether there are differences
between the different subtypes of beta blockers or whether beta blockers have
differential effects on younger and elderly patients.
(Prototype: Atenolol)
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COCHRANE ON BB in HTN
Results showed that the risk of all-cause mortality was not different between first-
line beta blockers and placebo, diuretics, or inhibitors of the renin angiotensin
system but was higher for beta blockers compared with calcium blockers.
(Prototype: Atenolol)
Comparative drug RR of all-cause mortality
for beta blockers
95% CI
Placebo 0.99 0.88-1.11
Diuretics 1.04 0.91-1.19
ACE inhibitors/ARBs 1.10 0.98-1.24
Calcium blockers 1.07 1.00-1.14
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COCHRANE ON BB in HTN
The risk of total cardiovascular disease was lower for first-line beta blockers compared
with placebo but was significantly worse for beta blockers compared with calcium
blockers. There was no significant difference in this end point with beta blockers when
compared with either diuretics or ACE inhibitors/ARBs.
(Prototype: Atenolol)
Comparative drug RR of total CV disease forbeta blockers
95% CI
Placebo 0.88 0.79-0.97
Diuretics 1.13 0.99-1.13
ACE inhibitors/ARBs 1.00 0.72-1.38
Calcium blockers 1.18 1.08-1.29
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COCHRANE ON BB in HTN
The lower risk of total cardiovascular disease
with beta blockers compared with placebo was
primarily a reflection of the significant decrease
in stroke, whereas coronary heart disease (CHD)
risk was not significantly different between beta
blockers and placebo.
Similarly, the increase in total cardiovascular
disease with beta blockers compared with
calcium blockers was due to an increase in
stroke with the beta blockers.
There was also an increase in stroke with beta
blockers as compared with inhibitors of the
renin angiotensin system. CHD was not
significantly different between beta blockers and
diuretics, calcium blockers, or renin-angiotensin-
system inhibitors.
(Prototype: Atenolol)
Comparative
drug
RR of stroke
for beta
blockers
95% CI
Placebo 0.80 0.66-0.96
Diuretics 1.17 0.65-2.09
ACE
inhibitors/
ARBs
1.30 1.11-1.53
Calcium
blockers
1.24 1.11-1.40
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COCHRANE ON BB in HTN
The authors conclude that "beta blockers are inferior to various calcium-channel
blockers for all-cause mortality, stroke, and total cardiovascular events and to renin-
angiotensin-system inhibition for stroke."
Is age important?
Noting that a previous meta-analysis (by Khan and McAlister) found beta blockers
to be inferior to all other therapies only in elderly patients, they point out that this
claim relies heavily on the Medical Research Council trial in elderly hypertensivepatients, in which the dropout rate was 25%. They say: "At present, there are
insufficient data to make a valid comparison of beta-blocker effects on younger vs
elderly patients, although this is an important hypothesis."
(Prototype: Atenolol)
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COCHRANE ON BB in HTN
Are there differences between beta blockers?
They point out that of the 40,245 participants using beta blockers in this review,
atenolol was used by 30,150 (75%). "Due to the paucity of data using beta blockers
other than atenolol, it is not possible to say whether the effectiveness (or lack
thereof) and (in)tolerability of beta blockers seen here is a property of atenolol or is
a class effect of beta blockers across the board.
The authors note that the information reported in the trials considered in thisreview was insufficient to explore the effect of race or ethnicity, as most trial
participants were white.
(Prototype: Atenolol)
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THE ASCOT-BPLA TRIAL
Evidence No.2
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ASCOT-BPLA TRIAL
Anglo-Scandinavian Cardiac Outcomes TrialBlood Pressure Lowering Arm (ASCOT-
BPLA) trial have confirmed preliminary findings showing that an antihypertensive
strategy based on amlodipine, with perindopril added as required, significantly
reduced all-cause mortality and other cardiovascular end points, including stroke,
compared with an atenolol-based strategy, with the
diuretic bendroflumethiazide added as required.
A 10% reduction in nonfatal MI and fatal coronary heart disease (CHD), the primary
end point of the trial, did not reach statistical significance, a finding that the
researchers attribute to the early stop of the trial.
A reduction in all-cause mortality seen with the amlodipine/perindopril strategy
caused the trial to be stopped in November 2004.
(Prototype: Atenolol)
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ASCOT-BPLA TRIAL
(Prototype: Atenolol)
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ASCOT-BPLA:
PRIMARY AND SECONDARY END POINTS
(Prototype: Atenolol)
End point Amlodipine-
based regimen
Atenolol-based
regimen
Unadjusted hazard
ratio (95% CI)
p
Primary end point
(n)
429 474 0.90 (0.79-1.02) 0.1052
Fatal and nonfatal
stroke (n)
327 422 0.77 (0.66-0.89) 0.0003
Total CV events and
procedures (n)
1362 1602 0.84 (0.78-0.90)
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ASCOT-BPLA:
PRIMARY AND SECONDARY END POINTS
(Prototype: Atenolol)
End point Amlodipine-
based regimen
Atenolol-based
regimen
Unadjusted
hazard ratio (95%CI)
p
New-onset
diabetes
567 799 0.70 (0.63-0.78)
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NEW ONSET DIABETES: TRIALS
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ASCOT-BPLA:
PRIMARY AND SECONDARY END POINTS
(Prototype: Atenolol)
Patients with new or prior diabetes were = 3x more likely to have a
CV event than those without diabetes.
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THE CAFE TRIAL
Evidence No.3
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CAFE TRIAL
(Prototype: Atenolol)
Conduit Artery Function Evaluation (CAFE), a sub-
study of the ASCOT, which compared the BB atenolol
+/- a diuretic with a regimen based
on amlodipine +/- without the ACEI, perindopril.
CAFE findings showed substantial reductions in
central aortic BP with amlodipine + perindopril overatenolol + diuretic, despite very similar brachial BPs
between the groups.
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CAFE TRIAL
(Prototype: Atenolol)
The greater vasodilation seen with amlodipine-based
treatment might translate into a reduction in the strength of
the reflected wave velocity from the periphery, thereby
reducing central arterial pressures.
Williams pointed out that a 3- to 4-mm-Hg difference in BP
seen between groups in central aortic pressures translates
into roughly a 25% difference in stroke risk (similar to the 27%reduction in stroke risk seen in ASCOT in the amlodipine/perindopril arm,
supporting the possibility that this difference in central pressures may
explain the differences seen in outcomes between groups).
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CAFE TRIAL
(Prototype: Atenolol)
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CAFE TRIAL
(Prototype: Atenolol)
Measure Amlodipine-based
vs Atenolol-based
regimen (mm Hg)
95% CI p
Brachial systolic BP 0.7 -0.4 to 1.7 0.2
Central aortic
systolic BP
4.3 3.3 to 5.4
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THE CACHET TRIAL
Evidence No.4
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CACHET TRIAL
(Prototype: Atenolol)
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CACHET TRIAL
(Prototype: Atenolol)
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EUROPEAN SOCIETY REACTS
The Impact
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WHAT THE ESC/ESH SAYS
BB vs CCB:
In support ofASCOT-BPLA
INVEST trial: also showed equal incidence of CVevents in patients with CAD in whom treatment was
started with a CCB (verapamil, often + ACE I) or with
a BB (atenolol often + D)
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WHAT THE ESC/ESH SAYS
BB vs ARB: In the LIFE study in more than 9000 hypertensive patients
with electrocardiographic left ventricular hypertrophy mean
blood pressure was reduced to the same degree in the groups
in which treatment was initiated with either losartan or the b-blocker atenolol.
Over the about 5 years of follow-up losartan-treated patients
showed a significant 13% reduction in major cardiovascular
events (the primary end point) with no difference in theincidence of myocardial infarction, but a 25% difference in the
incidence of stroke.
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WHAT THE ESC/ESH SAYS
The LIFE study and the ASCOT study, both of which showedsuperiority of an ARB, and, respectively, a CCB over therapy
initiated by a BB as far as stroke (LIFE) or stroke and mortality
(ASCOT) were concerned.
These two large trials have strongly influenced a recent meta-analysis which concluded that BB initiated therapy is inferior
to others in stroke prevention, but not in prevention of
myocardial infarction and reduction in mortality.
On the basis of a similar meta-analysis, the National Institutefor Health and Clinical Excellence (NICE) in the United
Kingdom has advised the use of b-blockers only as fourth line
antihypertensive agents.
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WHAT THE ESC/ESH SAYS
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THE VERDICT
efficacy on CV endpoints (esp. Stroke) 1,3,4
Metabolically unfriendly - r/o New onset DM 1
Least cost effective 2
No significant difference in all cause mortality
compared to A or D but higher than with CCB 3
Risk for CV disease worse with BB compared to CCB 3
Should be used as 4th line drugs in HTN 2
Source: 1 ASCOT-BPLA trial, LIFE study2 NICE guidelines CG34:Hypertension3 Cochrane Review: BB should not be fist line for HTN , Jan 24, 2007
4
CAFE trial: Circulation, Mar 2006; CACHET trial: Stroke 2006
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BUT, IS IT SO???LETS LOOK BACK
The future looks bleak for Beta Blockers..
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COCHRANE ON BB in HTN
(Prototype: Atenolol)
Comparative drug RR of all-cause mortality forbeta blockers
95% CI
Placebo 0.99 0.88-1.11
Diuretics 1.04 0.91-1.19
ACE inhibitors/ARBs 1.10 0.98-1.24
Calcium blockers 1.07 1.00-1.14
Comparative drug RR of total CV disease for beta
blockers
95% CI
Placebo 0.88 0.79-0.97
Diuretics 1.13 0.99-1.13
ACE inhibitors/ARBs 1.00 0.72-1.38
Calcium blockers 1.18 1.08-1.29
Comparative
drug
RR of stroke for
beta blockers
95% CI
Placebo 0.80 0.66-0.96
Diuretics 1.17 0.65-2.09
ACE inhibitors/
ARBs
1.30 1.11-1.53
Calcium
blockers
1.24 1.11-1.40
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ASCOT-BPLA TRIAL
(Prototype: Atenolol)End point Amlodipin
e-based
regimen
Atenolol-
based
regimen
Unadjusted
hazard ratio
(95% CI)
p
Primary end
point (n)
429 474 0.90 (0.79-
1.02)
0.1052
Fatal and
nonfatal
stroke (n)
327 422 0.77 (0.66-
0.89)
0.0003
Total CV
events and
procedures
(n)
1362 1602 0.84 (0.78-
0.90)
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NEW ONSET DIABETES: TRIALS
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CAFE & CACHET TRIALS
(Prototype: Atenolol)
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ATENOLOL
Developed in 1976, USFDA approved in 1981.
Short acting beta blocker.
Good BP but doesnt improve outcome.
Bad safety profile in stroke1
CBF2, less reduction in central aortic pressure3
Metabolically unsafe - incidince of new onset DM4
Bad safety profile in elderly5
Must NOT be used in uncomplicated HTN.
Source: 1 ASCOT-BPLA trial2 CACHET trial3 CAFE trial4 LIFE trial, ASCOT-BPLA trial
5
MRC study
BETA BLOCKERS IN HTN
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BETA BLOCKERS IN HTN
WHERE DO THEY STAND??
Atenolol is BAD as a first line drug in uncomplicated HTN.
NOT ALL BETA BLOCKERS ARE.
The outcomes seen in the recent clinical trials seem to be
more of a DRUG EFFECT than a CLASS EFFECT!!
Newer BB, esp. vasodilatory BB like nebivolol hold a
promising future for these drugs.
Lack of clinical data on these drugs has limited their
recommendation by international guidelines.
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THE EVIDENCE IN FAVOUR OF BB
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THE EVIDENCE IN FAVOUR OF BB
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THE EVIDENCE IN FAVOUR OF BB
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THE EVIDENCE IN FAVOUR OF BB
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THE EVIDENCE IN FAVOUR OF BB
ESC-ESH 2007 Guidelines state: Also, in the INVEST trial, a treatment strategy based on the initial
administration of a b-blocker followed by the addition, in mostpatients, of a thiazide diuretic was accompanied by an incidence of all
cardiovascular and cause-specific events similar to that of a treatment
initiated with the calcium antagonist verapamil followed by the
addition of the ACE inhibitor trandolapril.
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THE EVIDENCE IN FAVOUR OF BB
ESC-ESH 2007 Guidelines state: Finally, a recent meta-analysis shows that, when compared with
placebo, BB based therapy did indeed reduce stroke significantly.
This suggests that at least part of the inferiority of the b-blocker-
thiazide combination reported in ASCOT may be due to a lesser blood
pressure reduction, particularly of central blood pressure, that
occurred in this trial with this therapeutic regimen.
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JNC 7 & ESC-ESH 2007 AGREE
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THE LAST WORD
Newer BBs especially the vasodilatory BB like Nebivolol and
Carvedilol are metabolically neutral they DO NOT increase
the incidence of newer diabetics.
Newer BBs in fact the central aortic pressure thus the risk
of stroke by > 25%.
Newer BBs (nebivolol) can be used in elderly even with a
reduced EF (SENIORS trial, J. Am. Coll. Cardiol. 2009;53;2150-2158).
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THE LAST WORD
Newer BBs can be used in young HTNs/preHTNs to CO and
thus prevent worsening of HTN or development of HTN.
BB though conventionally placed as Category C drugs in
pregnancy, hold promise as newer BBs are being developed
with better safety profiles (Labetolol BB OC in Pregnancy).
Newer BBs like Nebivolol, Carvedilol and Metoprolol can be
safely used in Diabetes as they do not exacerbate
hypoglycaemia unlike conventional BB (Ppnl, Atenolol).
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THE LAST WORD
The sins of one (Atenolol) must not be made an excuse for the
execution of many (BB as a class).
The bad profiles seen in recent trials seems to be more of a
DRUG EFFECT than a CLASS EFFECT.
BB can remain a first line drug in HTN as HTN remains a
leading cause of HF and BB are a DOC in HF as well (? dual
benefit).
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THE LAST WORD
In anyone with any type of cardiac condition BB remain THE
first line drug of choice (JNC7, ESC-ESH 2007 guidelines).
In uncomplicated HTN (if such a term exists!), there are many
other drugs that have carved a niche for themselves, namely
ACEIs, ARBs, CCBs and Diuretics.
Diuretics remain the first line drugs in uncomplicated HTN, a
result largely of their low cost rather than improved outcome.
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QUESTIONS ?
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