In the name of Allah, Most Gracious, Most Merciful

BETA BLOCKERS
- IN HYPERTENSION
- Dr. Mohammed Sadiq Azam First yr. PG M-I

HISTORY
1948: Ahlquist classified adrenergic receptors into and 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 1 selective. 2003: BB become the most controversial antiHTNs!! 2010: ??????

PHYSIOLOGY OF RECEPTORS
Receptor Location 1 Heart, JG cells of kidney Dobutamine 2 Bronchi, Blood vessels, Uterus, GIT, Urinary tract, Eye Salbutamol Terbutaline 3 Adipose tissue

Selective agonist

BRL37344

Selective antagonist Potency of NA as agonist

Role

Metoprolol Atenolol Strong

Cardiac + Inotropic + Chronotropic

ISI118551 -methyl propronlol Weak

Vasodilatation Bronchodilatation Glucagon levels

CGP20712A (+B1) ICI118551 (+B2) Strong

Lipolysis

CLASSIFICATION OF BLOCKERS
1. Non selective (1 & 2):
Without ISA :
Propronolol Sotalol

Timolol Pindolol Labetolol

Carvedilol

With ISA:

With additional blocking property:

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

CLASSIFICATION OF BLOCKERS
2. Cardioselective (1):
Metoprolol

Acebutolol
Esmolol

Atenolol
Bisoprolol

Betaxolol
Celiprolol Butoxamine

3.

Selective (2):

ICI118551

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

CLASSIFICATION OF BLOCKERS

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

CLASSIFICATION OF BLOCKERS

GENERATION First Second

CLASS Non selective Selective

COMPOUND Propronolol Metoprolol

Third

Beta blocker - vasodilator

Carvedilol Bucindolol Nebivolol

(Ref: Braunwald, Drugs in treatment of Heart Failure, Heart Disease, p590:t23-11,7e:2005)

PHARMACODYNAMICS
On Heart:
HR, Force of contraction, Cardiac Output

(Prototype: Propronlol)

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. rate of DP in ectopic foci

Refractory period & automaticity -

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
(Prototype: Propronlol)

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.

PHARMACODYNAMICS
(Prototype: Propronlol)

Mechanisms of Anti Hypertensive action:

1. Initially: TPR and C.O (15-20%) => little change in BP

2.

Chronic use: resistance vessels adapt TPR , CO

=> BP

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

PHARMACOKINETICS
(Prototype: Propronlol)

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 (

BA with meals as food FPM

on chronic use) doses

Metabolism is saturatable. BA
Plasma protein binding > 90%

with

Excretion in urine as Glucronides

DRUG INTERACTION
(Prototype: Propronlol)

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

ADR & CONTRA INDICATIONS

(Prototype: Propronlol)

Fatigue - MC ADR Myocardial insufficiency C/I in severe HF in patients with SSS Bradycardia -

variant angina unopposed mediated coronary VC

Impairment of carbohydrate tolerance in pre diabetics.

Altered plasma lipid profile TGL , LDL HDL

Sudden withdrawal rebound HTN,

Worsening of PVD

angina, sudden death

exercise capacity 2 mediated VD to skeletal muscle

ADR & CONTRA INDICATIONS

(Prototype: Propronlol)

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

CCB/ACEI

r/o suicide compared to

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??

WHAT THE JNC 7 SAYS

WHAT THE JNC 7 SAYS

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.

COCHRANE ON BB in HTN
(Prototype: Atenolol)
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
ACE inhibitors/ARBs Calcium blockers

1.04
1.10 1.07

0.91-1.19
0.98-1.24 1.00-1.14

COCHRANE ON BB in HTN
(Prototype: Atenolol)
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 beta blockers
0.88 1.13 1.00 1.18

95% CI

Placebo Diuretics ACE inhibitors/ARBs Calcium blockers

0.79-0.97 0.99-1.13 0.72-1.38 1.08-1.29

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.

(Prototype: Atenolol)

Comparative drug

RR of stroke for beta blockers

0.80 1.17 1.30

95% CI

Placebo Diuretics ACE inhibitors/ ARBs Calcium blockers

0.66-0.96 0.65-2.09 1.11-1.53

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-angiotensinsystem inhibitors.

1.24

1.11-1.40

COCHRANE ON BB in HTN
(Prototype: Atenolol)
The authors conclude that "beta blockers are inferior to various calcium-channel

blockers for all-cause mortality, stroke, and total cardiovascular events and to reninangiotensin-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."

COCHRANE ON BB in HTN
(Prototype: Atenolol)

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
(Prototype: Atenolol)
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.

ASCOT-BPLA TRIAL
(Prototype: Atenolol)

ASCOT-BPLA: PRIMARY AND SECONDARY END POINTS

(Prototype: Atenolol)
End point Amlodipinebased regimen 429 Atenolol-based regimen 474 Unadjusted hazard ratio (95% CI) 0.90 (0.79-1.02) p

Primary end point (n) Fatal and nonfatal stroke (n) Total CV events and procedures (n)

0.1052

327

422

0.77 (0.66-0.89)

0.0003

1362

1602

0.84 (0.78-0.90)

<0.0001

All-cause mortality (n)

738

820

0.89 (0.81-0.99)

0.025

ASCOT-BPLA: PRIMARY AND SECONDARY END POINTS

(Prototype: Atenolol)

End point

Amlodipinebased regimen

Atenolol-based regimen

Unadjusted p hazard ratio (95% CI)

0.70 (0.63-0.78) <0.0001

New-onset diabetes

567

799

NEW ONSET DIABETES: TRIALS

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.

Evidence No.3

THE CAFE TRIAL

CAFE TRIAL
(Prototype: Atenolol)

Conduit Artery Function Evaluation (CAFE), a substudy 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
(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).

CAFE TRIAL
(Prototype: Atenolol)

CAFE TRIAL
(Prototype: Atenolol)
Measure Amlodipine-based vs Atenolol-based regimen (mm Hg) 0.7 95% CI p

Brachial systolic BP

-0.4 to 1.7

0.2

Central aortic systolic BP Central aortic pulse pressure

4.3

3.3 to 5.4

<0.0001

3.0

2.1 to 3.9

<0.0001

Evidence No.4

THE CACHET TRIAL

CACHET TRIAL
(Prototype: Atenolol)

CACHET TRIAL
(Prototype: Atenolol)

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)

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 bblocker 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.

WHAT THE ESC/ESH SAYS

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 metaanalysis 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.

WHAT THE ESC/ESH SAYS

THE VERDICT
efficacy on CV endpoints (esp. Stroke) 1,3,4

Metabolically unfriendly Least cost effective 2

r/o New onset DM 1

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

COCHRANE ON BB in HTN
(Prototype: Atenolol)
Comparative drug RR of all-cause mortality for beta blockers 95% CI

Placebo Diuretics

0.99 1.04 Comparative drug 1.10

0.88-1.11 0.91-1.19 RR of total CV disease for beta blockers 0.98-1.24 0.88 1.13 1.00 1.18

95% CI

ACE inhibitors/ARBs Placebo Calcium blockers Diuretics

1.07

1.00-1.14

Comparative 0.79-0.97 drug

RR of stroke for beta blockers

95% CI

Placebo

0.99-1.13 0.72-1.38

0.80

0.66-0.96

ACE inhibitors/ARBs Calcium blockers

Diuretics

1.17
1.30

0.65-2.09
1.11-1.53

1.08-1.29 ACE inhibitors/ ARBs

Calcium blockers

1.24

1.11-1.40

ASCOT-BPLA TRIAL
(Prototype: Atenolol)
End point Amlodipin e-based regimen 429 Atenololbased regimen 474 Unadjusted hazard ratio (95% CI) 0.90 (0.791.02) p

Primary end point (n)

0.1052

Fatal and nonfatal stroke (n)

Total CV events and procedures (n) All-cause mortality (n)

327

422

0.77 (0.660.89)

0.0003

1362

1602

0.84 (0.780.90)

<0.0001

738

820

0.89 (0.810.99)

0.025

NEW ONSET DIABETES: TRIALS

CAFE & CACHET TRIALS

(Prototype: Atenolol)

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 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

THE EVIDENCE IN FAVOUR OF BB

THE EVIDENCE IN FAVOUR OF BB

THE EVIDENCE IN FAVOUR OF BB

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.

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 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.

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-blockerthiazide 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.

JNC 7 & ESC-ESH 2007 AGREE

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 of stroke by > 25%. the risk

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.

QUESTIONS ?

THANK YOU

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