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.
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.
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)
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