TREATMENT of HYPERTENSION: ROLE OF BETA BLOCKERSDR. SUJAY IYERI YEAR PGGENERAL MEDICINE

TABLE OF CONTENT

Introduction Pharmacodynamics & Pharmacokinetics Specific Agents Adverse Effects Clinical Use

History Concerns End of the Road? Indications for use in Hypertension Conclusion

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.

ADRENERGIC BETA RECEPTORSβ1 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.

ADRENERGIC BETA RECEPTORSb2 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.

ADRENERGIC BETA RECEPTORS

β3 RECEPTORS Located mainly in the adipose tissues. Enhancement of lipolysis. Thermogenesis in skeletal muscles.

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.

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.

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.

PHARMACODYNAMICSMETABOLIC & 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.

SPECIFIC AGENTSPROPRANOLOL: 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.

SPECIFIC AGENTSPARTIAL 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.

ADVERSE EFFECTSCARDIAC 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.

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.

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

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.

TIMELINE OF HYPERTENSION

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.

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.

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.

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.

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.

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.

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.

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.

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.

“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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