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BETA BLOCKERS
IN HYPERTENSION
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!!
PHYSIOLOGY OF RECEPTORS
Receptor Location 1 Heart, JG cells of kidney Dobutamine Metoprolol Atenolol 2 Bronchi, Blood vessels, Uterus, GIT, Urinary tract, Eye Salbutamol Terbutaline 3 Adipose tissue
BRL37344
ISI118551 CGP20712A -methyl propronlol (+B1) ICI118551 (+B2) Weak Strong Lipolysis
Strong
CLASSIFICATION OF BLOCKERS
1. Non selective (1 & 2):
Without ISA :
Propronolol Sotalol Timolol Pindolol Labetolol Carvedilol
With ISA:
(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 ICI118551
3. Selective (2):
(Ref: Tripathi KD, antiadrenergic drugs, Essentials of Med. Pharmacology, p124, 5e:2003)
CLASSIFICATION OF BLOCKERS
CLASSIFICATION OF BLOCKERS
PHARMACODYNAMICS
On Heart:
(Prototype: Propronlol) 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
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)
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 ( 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
(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
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
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
TO BE OR NOT TO BE??
EBM
Evidence no.1
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 calciumchannel blockers, renin-angiotensin-system inhibitors, and thiazide diuretics.
Most of the evidence for these conclusions comes from trials whereatenololwas the beta blocker used, and it is not known at present whether there are differences between the different
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 Comparative drugRRblockers. 95% CI compared with calcium of all-cause mortality for beta blockers Placebo Diuretics ACE inhibitors/ARBs 0.99 1.04 1.10 0.88-1.11 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.
RR of total CV disease for beta blockers 0.88 1.13 95% CI
Comparative drug
Placebo Diuretics
Calcium blockers
1.18
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. 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
(Prototype: Atenolol)
Comparativ RR of 95% CI e drug stroke for beta blockers Placebo 0.80 0.66-0.96 0.65-2.09 1.11-1.53
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 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 theMedical Research Counciltrial 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
COCHRANE ON BB in HTN
(Prototype: Atenolol)
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
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 onamlodipine, withperindopriladded as required, significantly reduced all-cause mortality and other cardiovascular end points, including stroke, compared with anatenolol-based strategy, with the diureticbendroflumethiazideadded 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
ASCOT-BPLA TRIAL
(Prototype: Atenolol)
Primary end point (n) Fatal and nonfatal stroke (n) Total CV events and procedures (n) All-cause mortality (n)
0.1052
327
422
0.77 (0.66-0.89)
0.0003
1362
1602
0.84 (0.78-0.90)
<0.0001
738
820
0.89 (0.81-0.99)
0.025
End point
New-onset diabetes
<0.0001
Patients with new or prior diabetes were = 3x more likely to have a CV event than those without diabetes.
Evidence No.3
CAFE TRIAL
(Prototype: Atenolol)
Conduit Artery Function Evaluation(CAFE), a sub-study of theASCOT, which compared the BBatenolol +/- a diuretic with a regimen based onamlodipine+/- without the ACEI,perindopril. CAFE findings showed substantial reductions in central aortic BP with amlodipine + perindopril over atenolol + diuretic, despite very similar brachial BPs
CAFE TRIAL
(Prototype: Atenolol)
The greater vasodilation seen with amlodipinebased 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 Amlodipinebased vs Atenololbased regimen (mm Hg) 0.7 95% CI p
-0.4 to 1.7
0.2
4.3
3.3 to 5.4
<0.0001
2.1 to 3.9
<0.0001
Evidence No.4
CACHET TRIAL
(Prototype: Atenolol)
CACHET TRIAL
(Prototype: Atenolol)
The Impact
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)
THE VERDICT
efficacy on CV endpoints (esp. Stroke)
1,3,4
No significant difference in all cause mortality compared to A or D but higher 3 than with CCB LIFE study Source: 1 ASCOT-BPLA trial, Risk for CV disease worse with BB compared to CCB 3
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
COCHRANE ON BB in HTN
(Prototype: Atenolol)
Comparative drug RR of all-cause mortality for beta blockers 0.99 95% CI
Placebo
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
Diuretics 1.04 Comparative drug ACE inhibitors/ARBs 1.10 Placebo Calcium blockers Diuretics
OL OL EN AT
95% CI 1.07 0.99-1.13 0.72-1.38
Placebo 0.80 1.17 Diuretics
1.18
1.11-1.40
ASCOT-BPLA TRIAL
(Prototype: Atenolol)
End point Amlodipi Atenolol- Unadjuste ne-based based d hazard regimen regimen ratio (95% CI) p
Primary end point (n) Fatal and nonfatal stroke (n) Total CV events and procedure s (n) All-cause mortality (n)
429
474
327
422
1362
1602
OL OL EN AT
0.77 (0.660.89) 0.0003 0.84 (0.78- <0.0001 0.90) 0.89 (0.810.99) 0.025
0.90 (0.791.02)
0.1052
738
820
OL OL EN AT
OL OL EN AT
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
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