Beta Blockers in HTN

In the name of Allah, Most Gracious, Most Merciful

B E T A B L OCK E R S
- I N H Y P E R T E NS I ON

- Dr. Mohammed Sadiq Azam
First yr. PG
M-I

HISTORY
• 1948: Ahlquist classified adrenergic receptors
into α and β receptors.
• 1958: Dichloroisoprenaline (DCI) – First BB
• 1963: Therapeutic breakthrough, Propronolol
introduced by J.W.Black
• 1980: BB become the most popular antiHTNs
after diuretics. Practolol – First β1 selective.
• 2003: BB become the most controversial
antiHTNs!!
• 2010: ??????

PHYSIOLOGY OF β RECEPTORS

Receptor β1 β2 β3
Location Heart, Bronchi, Blood Adipose tissue
JG cells of kidney vessels, Uterus, GIT,
Urinary tract, Eye
Selective agonist Dobutamine Salbutamol BRL37344
Terbutaline
Selective antagonist Metoprolol ISI118551 CGP20712A (+B1)
Atenolol α-methyl propronlol ICI118551 (+B2)
Potency of NA as Strong Weak Strong
agonist
Role Cardiac Vasodilatation Lipolysis
+ Inotropic Bronchodilatation
+ Chronotropic ↑ Glucagon levels

CLASSIFICATION OF β BLOCKERS
1. Non selective (β1 & β2):
– Without ISA :
» Propronolol
» Sotalol
» Timolol
– With ISA:
» Pindolol
– With additional α blocking property:
» Labetolol
» Carvedilol

(Ref: Tripathi KD, β antiadrenergic drugs, Essentials of Med. Pharmacology, p124, 5e:2003)

1. Cardioselective (β1):
– Metoprolol
– Acebutolol
– Esmolol
– Atenolol
– Bisoprolol
– Betaxolol
– Celiprolol
2. Selective (β2):
– Butoxamine
– ICI118551

(Ref: Tripathi KD, β antiadrenergic drugs, Essentials of Med. Pharmacology, p124, 5e:2003)


(Ref: Braunwald, Systemic Hypertension:Therapy, Heart Disease, p1002:f38-11,7e:2005)


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)

PHARMACODYNAMICS
(Prototype: Propronlol)
• 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.

PHARMACODYNAMICS

• On Blood vessels:
– Inhibits VD & ↓ BP caused by Isoprenaline
– Augments ↑ BP caused by Adrenaline
– Re-reversal of vasomotor reversal seen after α-blockade (Reverse Dale)
– No direct effect on blood vessels => little acute change in BP
– Prolonged use: BP ↓ in hypertensive subjects but NOT in normotensives.

PHARMACODYNAMICS

• Mechanisms of Anti Hypertensive action:
– 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 β-mediated
release.
3. ↓ β 1 mediated renin release from kidney (upto 60% in BB with ISA - )
4. Central action ↓ sympathetic outflow

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

DRUG INTERACTION

• Additive depression of SA node and AV conduction with digitalis
and verapamil .
• Delayed recovery from hypoglycemia
• Unopposed α action - ↑ TPR
• Indomethacin/NSAIDs- Attenuate anti HTN action
• Cimitidine inhibits Ppnl metabolism.
• Ppnl ↓ metabolism by ↓ HBF
• Ppnl ↑ BA of CPZ by ↓ FPM

ADR & CONTRA INDICATIONS

• Fatigue - MC ADR
• ↑↑ Myocardial insufficiency – C/I in severe HF
• Bradycardia - ↑↑ in patients with SSS
• ↑ variant angina – unopposed α 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 – β2 mediated VD to skeletal muscle ↓
• Worsening of PVD

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)

And now…

THE MILLION DOLLAR QUESTION…

The Role of Beta Blockers in Hypertension…

TO BE OR NOT TO BE??

EBM

WHAT DOES EVIDENCE POINT AT??

Evidence no.1

THE COCHRANE REVIEW

COCHRANE ON BB in HTN
(Prototype: Atenolol)

• 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.


• 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.
Comparative drug RR of all-cause mortality 95% CI
for beta blockers

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

• 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.

Comparative drug RR of total CV disease for 95% CI
beta blockers

Placebo 0.88 0.79-0.97

Diuretics 1.13 0.99-1.13



• The lower risk of total cardiovascular disease
with beta blockers compared with placebo was
primarily a reflection of the significant decrease Comparative RR of stroke 95% CI
drug for beta
in stroke, whereas coronary heart disease (CHD) blockers
risk was not significantly different between beta
blockers and placebo. Placebo 0.80 0.66-0.96
• Similarly, the increase in total cardiovascular
disease with beta blockers compared with Diuretics 1.17 0.65-2.09

calcium blockers was due to an increase in
stroke with the beta blockers. ACE 1.30 1.11-1.53
inhibitors/
• There was also an increase in stroke with beta ARBs
blockers as compared with inhibitors of the
renin angiotensin system. CHD was not Calcium 1.24 1.11-1.40
blockers
significantly different between beta blockers
and diuretics, calcium blockers, or renin-
angiotensin-system inhibitors.


• 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 hypertensive
patients, 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."


• 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 this
review was insufficient to explore the effect of race or ethnicity, as most trial
participants were white.

Evidence No.2

THE ASCOT-BPLA TRIAL

ASCOT-BPLA TRIAL

• Anglo-Scandinavian Cardiac Outcomes Trial—Blood 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.

ASCOT-BPLA TRIAL

ASCOT-BPLA:
PRIMARY AND SECONDARY END POINTS
End point Amlodipine- Atenolol-based Unadjusted hazard p
based regimen regimen ratio (95% CI)

Primary end point 429 474 0.90 (0.79-1.02) 0.1052
(n)

Fatal and nonfatal 327 422 0.77 (0.66-0.89) 0.0003
stroke (n)

Total CV events and 1362 1602 0.84 (0.78-0.90) <0.0001
procedures (n)

All-cause mortality 738 820 0.89 (0.81-0.99) 0.025
(n)

ASCOT-BPLA:

End point Amlodipine- Atenolol-based Unadjusted p
based regimen regimen hazard ratio (95%
CI)

New-onset 567 799 0.70 (0.63-0.78) <0.0001
diabetes

ASCOT-BPLA:

Patients with new or prior diabetes were = 3x more likely to have a
CV event than those without diabetes.

CAFE TRIAL

• 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 over
atenolol + diuretic, despite very similar brachial BPs
between the groups.

CAFE TRIAL

• 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).

CAFE TRIAL

CAFE TRIAL

Measure Amlodipine-based 95% CI p
vs Atenolol-based
regimen (mm Hg)

Brachial systolic BP 0.7 -0.4 to 1.7 0.2

Central aortic 4.3 3.3 to 5.4 <0.0001
systolic BP

Central aortic pulse 3.0 2.1 to 3.9 <0.0001
pressure

Evidence No.4

THE CACHET TRIAL

CACHET TRIAL

The Impact

EUROPEAN SOCIETY REACTS…

WHAT THE ESC/ESH SAYS…

BB vs CCB:
• In support of ASCOT-BPLA
• INVEST trial: also showed equal incidence of CV
events in patients with CAD in whom treatment was
started with a CCB (verapamil, often + ACE I) or with
a BB (atenolol often + D)


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 the
incidence of myocardial infarction, but a 25% difference in
the incidence of stroke.


• The LIFE study and the ASCOT study, both of which showed
superiority 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 Institute
for Health and Clinical Excellence (NICE) in the United
Kingdom has advised the use of b-blockers only as fourth line
antihypertensive agents.

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 study
2 – NICE guidelines – CG34:Hypertension
3 – Cochrane Review: BB should not be fist line for HTN , Jan 24, 2007
4 – CAFE trial: Circulation, Mar 2006; CACHET trial: Stroke 2006

The future looks bleak for Beta Blockers..

BUT, IS IT SO???
LETS LOOK BACK…

Comparative drug RR of all-cause mortality for 95% CI
beta blockers

Placebo 0.99 0.88-1.11

Diuretics 1.04 0.91-1.19

OL
Comparative drug RR of total CV disease for beta 95% CI

OL
blockers

EN
Comparative RR of stroke for 95% CI
Placebo 0.88 0.79-0.97

AT
Calcium blockers 1.07 1.00-1.14 drug beta blockers

Diuretics 1.13 0.99-1.13
Placebo 0.80 0.66-0.96

Diuretics 1.17 0.65-2.09

ACE inhibitors/ 1.30 1.11-1.53
ARBs

Calcium 1.24 1.11-1.40
blockers

ASCOT-BPLA TRIAL
End point Amlodipin Atenolol- Unadjusted p
e-based based hazard ratio
regimen regimen (95% CI)

Primary end 429 474 0.90 0.1052
point (n) (0.79-1.02)

OL
Fatal and 327 422 0.77 0.0003

OL
nonfatal (0.66-0.89)

EN
stroke (n)

AT
Total CV 1362 1602 0.84 <0.0001
events and (0.78-0.90)
procedures
(n)

All-cause 738 820 0.89 0.025
mortality (0.81-0.99)
(n)

NEW ONSET DIABETES: TRIALS

OL OL
AT EN

CAFE & CACHET TRIALS

OL OL
AT EN

ATENOLOL
• Developed in 1976, USFDA approved in 1981.
• Short acting beta blocker.
• Good ↓ BP but doesn’t 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 trial
2 – CACHET trial
3 – CAFE trial
4 – LIFE trial, ASCOT-BPLA trial
5 – MRC study

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.

THE EVIDENCE IN FAVOUR OF BB

• ESC-ESH 2007 Guidelines state:
– Both the LIFE and the ASCOT studies were characterized by a design
implicating early use of combination therapy, so that the vast majority
of patients randomized to a BB actually received a BB-thiazide
combination.
– A similar combination was often used in the chlorthalidone treatment
group of the ALLHAT trial, which failed to find inferiority of this
combination even concerning stroke prevention.


– Also, in the INVEST trial, a treatment strategy based on the initial
administration of a b-blocker followed by the addition, in most
patients, 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.


– 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.

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).

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).

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).

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.

THANK YOU

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Beta Blockers in HTN

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