beta blockers

1. TREATMENT of
HYPERTENSION:
ROLE OF BETA
BLOCKERSDR. SUJAY IYER
I YEAR PG
GENERAL MEDICINE

2. TABLE OF CONTENT
 Introduction
 Pharmacodynamics & Pharmacokinetics
 Specific Agents
 Adverse Effects
 Clinical Use
 History
 Concerns
 End of the Road?
 Indications for use in Hypertension
 Conclusion

3. INTRODUCTION
 Beta Blockers are competitive antagonists that block the receptor site for
endogenous catecholamines on the adrenergic beta receptors.
 Some are partial agonists while most are pure antagonists.
 Beta blockers differ in their relative affinity for β1 and b2 receptors.

4. ADRENERGIC BETA RECEPTORS
β1 RECEPTORS
 Located mainly in the heart and the kidneys.
 Stimulates viscous, amylase-filled secretions from salivary glands.
 Increases cardiac output:
 (+) Chronotropic effect.
 (+) Inotropic effect.
 (+) Dromotropic effect.
 Renin release from juxtaglomerular cells.
 Lipolysis in adipose tissue.
 Relaxation of urinary bladder.

5. ADRENERGIC BETA RECEPTORS
b2 RECEPTORS
 Located mainly in the lungs, gastrointestinal tract, liver, uterus, vascular
smooth muscle and skeletal muscle.
 Muscular system:
 Smooth muscle relaxation – Delay in digestion and micturition, inhibits labour,
facilitate respiration.
 Blood vessels – Dilates arteries increasing perfusion.
 Circulatory system:
 Increases cardiac output.
 Eye: Increases intraocular pressure.
 GI: Glycogenolysis and gluconeogenesis with Insulin secretion.

6. ADRENERGIC BETA RECEPTORS
β3 RECEPTORS
 Located mainly in the adipose tissues.
 Enhancement of lipolysis.
 Thermogenesis in skeletal muscles.

7. PHARMACODYNAMICS &
PHARMACOKINETICS
PHARMACOKINETICS:
 Most of the drugs are absorbed well orally, peak concentrations occur 1-3
hours after ingestion.
 Bioavailability of most β-blockers is limited.
 Rapidly distributed.
 Some like Propranolol and Penbutolol are lipophilic and readily cross the
blood-brain barrier.
 Most of them have half-lives in the range of 3-10 hours with the exception
of Esmolol (10 minutes).
 Propranolol and Metoprolol are extensively metabolized in the liver.

8. PHARMACODYNAMICS
 The effects of β-blockers are due to occupation and blockade of β
receptors.
 Some actions may be due to partial agonist activity and local anesthetic
action.
CARDIOVASCULAR SYSTEM:
 β-blockers lower the blood pressure in patients with hypertension.
 Mechanism is not fully understood; but probably include suppression of
renin release and effects in the CNS. They do not lower BP in healthy
individuals.
 Prominent effect on the heart and valuable in the treatment of angina,
chronic heart failure and following myocardial infarction.
 Negative chronotropic, inotropic and dromotropic effect.

9. PHARMACODYNAMICS
 Oppose β2 mediated vasodilation which may acutely lead to rise in
peripheral vascular resistance from unopposed a receptor mediated
effects in the sympathetic nervous system.
RESPIRATORY TRACT:
 Increase in airway resistance, especially asthmatics.
 Selective β-blockers are advantageous over non-selective ones, however
none of them are sufficiently specific to completely avoid β2 -receptors.
EYE:
 Reduce intraocular pressure by decreasing aqueous humor production,
especially in Glaucoma.

10. PHARMACODYNAMICS
METABOLIC & ENDOCRINE EFFECTS:
 Inhibit lipolysis via sympathetic system.
 Glycogenolysis is partially inhibited in the liver by b2 blockade.
 Impairment of recovery from hypoglycaemia although b1 selective
antagonism may be less prone to it.
 Increased concentration of VLDL and decreased concentration of HDL,
although this is less prone in partial agonists.
EFFECTS NOT RELATED TO b BLOCKADE:
 Intrinsic sympathomimetic activity.
 Local anesthetic action.

11. SPECIFIC AGENTS
PROPRANOLOL:
 Prototypical non-selective b Blocker.
METOPROLOL AND ATENOLOL:
 β1-selective group.
 Preferred in COPD, Asthma, Diabetes and PVD over non-selective β-
Blockers.
NEBIVOLOL:
 Most highly selective β1-Blocker.
 Causes vasodilation.
 Increases insulin sensitivity and does not have adverse effect on lipid
metabolism.

12. SPECIFIC AGENTS
PARTIAL AGONISTS:
 Pindolol, Acebutolol, Cartelol, Penbutolol, etc.
 Likely to cause less bradycardia, less reduction in cardiac output,
abnormalities in plasma lipids and may produce vasodilation with increased
arterial compliance.
LABETALOL:
 Reversible a1 and b blocker with partial agonist activity.
 Decreases BP with having little effect over HR and CO.
CARVEDILOL:
 Non-selective b-Blocker with a1 adrenoreceptor blocking capacity.
 Decreased peripheral vascular resistance by causing vasodilation.
ESMOLOL:
 Ultra short-acting.

13. ADVERSE EFFECTS
CARDIAC EFFECTS:
 Exacerbation of acute heart failure.
 Negative chronotropic effect.
 b-Blocker withdrawl.
EXTRA-CARDIAC EFFECTS:
 Increased airway resistance.
 Exacerbation of peripheral artery disease.
 Facilitation of hypoglycaemia.
 Hyperkalemia
 Depression, fatigue, sexual dysfunction.
 Lipid metabolism and weight gain.

14. CLINICAL USE
 Hypertension.
 Ischemic heart disease.
 Cardiac arrhythmias.
 Heart failure.
 Glaucoma.
 Hyperthyroidism.
 Neurologic diseases.
 Other cardiovascular diseases: Obstructive cardiomyopathy, Dissecting
aortic aneurysm & Non-cardiac surgery.
 Miscellaneous: Portal hypertension & Infantile hemangioma.

15. HISTORY
 In the 1960s, Dr. James Black, a Scottish pharmacologist and his
associates started working on β-Blockers for treatment of angina.
 Pronethalol was released in 1963 but marketed only for life-threatening
conditions because of its side effects.
 Propranolol was launched in 1965 as Inderal. It quickly became a best-
selling drug , used to treat a wide range of cardiovascular diseases such
as angina, arrhythmia, hypertension and hypertrophic cardiomyopathy.
 In 1976, Atenolol was launched as ‘the ideal β-Blocker’ and soon replaced
Propranolol as the best selling heart drug.
 Metoprolol was made in 1969 and launched in the U.S in 1978.
 Bisoprolol and Carvedilol was released in 1986 and 1995 respectively.
 Dr. James Black was awarded the Nobel Prize in Medicine

16. HISTORY
 In ancient Indian Ayurvedic and Chinese medicine, a hard pulse felt on
palpation qualified as hypertension.
 Dr. Akbar Mahomed, an Irish-Indian, was the first physician to describe
essential hypertension in the late 19th century.
 The modern quantitaive concept of hypertension came along after the
discovery of the sphygnomanometer in the early 20th century.
 Even then, Hypertension was not considered a disease. President Franklin
D Roosevelt was given a clean bill of health with a BP of 220/120 mmHg.
 Veterans Administration Co-operative Research Study published in 1967
and 1970 was a landmark achievement in Medicine that established that
treating essential hypertension leads to lower incidence of CHF and
Stroke.

17. TIMELINE OF HYPERTENSION

18. TRIALS
 MRC Trial (1985): Use of Propranolol. To treat mild hypertension. Found
decreased risk of Stroke in comparison to placebo.
 SHEP (1991): Use of Atenolol. Benefits of treating isolated systolic
hypertension.
 TOMHS (1993): Use of Acebutolol. To compare BP lowering effects of six
treatment regimen. All six had sizeable BP reduction.
 UKPDS (1998): Use of Atenolol. To compare outcomes in hypertension
management among diabetics with Captopril. Equally effective outcomes.
 AASK (2002): Use of Metoprolol. To determine a suitable drug regimen in
hypertension control to prevent renal failure (Ramipril, Amlodipine).
Superiority of Ramipril over Metoprolol was only marginal.

19. CONCERNS
 ALLHAT (2002): Brought Thiazide diuretics to the forefront. Showed
reduced HF rates in hypertensives and dyslipidemics.
 Lancet Meta-Analysis (2004): Suggested that Atenolol did worse than
other antihypertensives in reducing stroke.
 Lancet Meta-Analysis (2005): In comparison with other antihypertensive
drugs, the effect of β blockers is less than optimum, with a raised risk of
stroke.
 Cochrane Meta-Analysis (2012): Beta blockers were inferior to other
antihypertensive drugs in reduction of cardiovascular disease.
 ASCOT BPLA(2005): CCB and ACEI are better than β blocker and
Thiazide diuretics.
 CAFE (2006): Amlodipine reduced central aortic pressure more than
Atenolol.

20. CONCERNS
 Based on the mounting evidence, β blockers were relegated to the
second-line in JNC-8 guidelines.
 Several theories have been proposed to explain the observed risk of
stroke:
 Pulse wave dyssynchrony leading to increased central aortic pressure.
 Less effective lowering of blood pressure.
 Visit-to-visit blood pressure instability.
 Unfavourable metabolic effects.

21. END OF THE ROAD?
 It is not yet time to give up on our old friend.
 A CMAJ Meta-Analysis in 2007 revealed that most of the previously observed
stroke risk was confounded by older populations.
 Most of the analysis on cardiovascular outcomes are derived from studies
using Atenolol.
 The MAPHY study showed that there is reduction in Stroke and Coronary
Artery Disease when using a long-acting β blocker.
 Vasodilatory β blockers may be safer!
 Many recent studies have shown that Nebivolol, Labetalol and Carvedilol
significantly reduce central aortic pressure.
 JCH 2013: Nebivolol, Carvedilol, Metoprolol
 Nature 2014: Losartan vs Carvedilol
 HJ 2015: Meta-analysis comparing vasodilating β blockers and non-vasodilating β
blockers.
 IJP 2012: Nebivolol.

22. INDICATIONS FOR USE IN
HYPERTENSION
DIABETES:
 The adverse metabolic and lipid consequences of traditional β blockers
raises some concerns.
 There seems to be a increased risk of new-onset diabetes with use of
Atenolol and Propranolol.
 Nebivolol and Carvedilol have shown neutral or beneficial effects on
metabolic parameters.
 GEMINI Trial.
 YESTONO Study.

23. INDICATIONS FOR USE IN
HYPERTENSION
CORONARY ARTERY DISEASE:
 β blockers not only reduce blood pressure but decrease the myocardial
oxygen demand.
 Effects of nonvasodilating β blockers on hyperemic coronary blood flow
are variable.
 Because of amelioration of rest and hyperemic coronary blood flow,
vasodilatory β blockers may be a better option than traditional β blockers in
patients with high coronary artery disease risk.

24. INDICATIONS FOR USE IN
HYPERTENSION
POST MYOCARDIAL INFARCTION:
 Recommended in the AHA guidelines.
 The value of β blockers in patients after MI has been established in BHAT
and CAPRICORN.
 Only Carvedilol is recommended among the vasodilatory β blockers.

25. INDICATIONS FOR USE IN
HYPERTENSION
HEART FAILURE:
 It is a serious natural progression of uncontrolled hypertension.
 3 β blockers are found to improve outcomes in patients with systolic heart
failure by inhibiting the negative effects associated with sympathetic
nervous system.
 Carvedilol: COPERNICUS (2001)
 Metoprolol: MERIT HF (1999)
 Bisoprolol: CIBIS (1999)
 Their benefits include reducing the risk of death and reducing symptoms,
improving clinical status and improving the overall well-being of the patient.
 Risk of mortality and rehospitalization are significantly lower with their use.

26. CONCLUSION
 β blockers may no longer be the undisputed leader in management of
hypertension.
 They still hold a special place in the treatment of cardiovascular diseases
including hypertension due to their cost-effectiveness and a reasonable
adverse effect profile.
 The reality of modern hypertension treatment is that most patients will
require multiple drugs. In patients with comorbidities, combination therapy
will be essential.
 Third generation vasodilating β blockers have many advantages over their
predecessors and should be preferred whenever possible.

27. “I wish I had my beta blockers handy”
- Dr. James Whyte Black (on being told that he had won the Nobel Prize)
THANK YOU 