Beta Blockers in HTN

In the name of Allah, Most Gracious, Most Merciful

BETA BLOCKERS- IN HYPERTENSION

- Dr. Mohammed Sadiq Azam

First yr. PGM - 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 β 1 β 2 β 3

Location Heart,JG cells of kidney

Bronchi, Blood vessels, Uterus, GIT, Urinary tract, Eye

Adipose tissue

Selective agonist Dobutamine SalbutamolTerbutaline

BRL37344

Selective antagonist MetoprololAtenolol

ISI118551α-methyl propronlol

CGP20712A (+B1)ICI118551 (+B2)

Potency of NA as agonist

Strong Weak Strong

Role Cardiac+ Inotropic+ Chronotropic

VasodilatationBronchodilatation Glucagon levels

Lipolysis

CLASSIFICATION OF β BLOCKERS

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

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)

2. Cardioselective (β1):– Metoprolol

– Acebutolol

– Esmolol

– Atenolol

– Bisoprolol

– Betaxolol

– Celiprolol

3. Selective (β2):– Butoxamine

– ICI118551


(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 CarvedilolBucindololNebivolol

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

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)

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: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 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)


THE MILLION DOLLAR QUESTION…And now…

TO BE OR NOT TO BE??The Role of Beta Blockers in Hypertension…

WHAT THE JNC 7 SAYS…

WHAT DOES EVIDENCE POINT AT??EBM

THE COCHRANE REVIEWEvidence no.1

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)


• 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 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


• 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

95% CI

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 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.


Relative risk of all-cause mortality for beta blockers vs placebo or other treatments

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


• 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.


THE ASCOT-BPLA TRIALEvidence No.2

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(Prototype: Atenolol)

ASCOT-BPLA: PRIMARY AND SECONDARY END POINTS


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) <0.0001

All-cause mortality (n)

738 820 0.89 (0.81-0.99) 0.025

ASCOT-BPLA: Primary and secondary end points





Atenolol-based regimen

Unadjusted hazard ratio (95% CI)

p

New-onset diabetes

567 799 0.70 (0.63-0.78) <0.0001

NEW ONSET DIABETES: TRIALS




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

THE CAFE TRIALEvidence No.3

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



• 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).



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 <0.0001

Central aortic pulse pressure

3.0 2.1 to 3.9 <0.0001

THE CACHET TRIALEvidence No.4

CACHET TRIAL (Prototype: Atenolol)


EUROPEAN SOCIETY REACTS…The Impact

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 study2 – NICE guidelines – CG34:Hypertension3 – Cochrane Review: BB should not be fist line for HTN , Jan 24, 20074 – CAFE trial: Circulation, Mar 2006; CACHET trial: Stroke 2006

BUT, IS IT SO???LETS LOOK BACK…

The future looks bleak for Beta Blockers..

COCHRANE ON BB in HTN(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



Relative risk of all-cause mortality for beta blockers vs placebo or other treatments

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



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

ATENOLOL

ASCOT-BPLA TRIAL (Prototype: Atenolol)


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)

<0.0001

All-cause mortality

(n)

738 820 0.89 (0.81-0.99)

0.025


ATENOLOL

NEW ONSET DIABETES: TRIALS

ATENOLOL

CAFE & CACHET TRIALS (Prototype: Atenolol)


ATENOLOL

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 trial3 – CAFE trial4 – LIFE trial, ASCOT-BPLA trial5 – 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.


• 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.


• 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.

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 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.

QUESTIONS ?

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Beta Blockers in HTN

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