beta blockers: role in hypertension

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TREATMENT of HYPERTENSION: ROLE OF BETA BLOCKERSDr. sujay iyerI year pgGeneral medicine

TABLE OF CONTENTIntroductionPharmacodynamics & PharmacokineticsSpecific AgentsAdverse EffectsClinical UseHistoryConcernsEnd of the Road?Indications for use in HypertensionConclusion

INTRODUCTIONBeta 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 1 and b2 receptors.

ADRENERGIC BETA RECEPTORS1 RECEPTORSLocated mainly in the heart and the kidneys.Stimulates viscous, amylase-filled secretions from salivary glands.Increases cardiac output:(+) Chronotropic effect.(+) Inotropic effect.(+) Dromotropic effect.(+) Bathmotropic effect.Renin release from juxtaglomerular cells.Lipolysis in adipose tissue.Relaxation of urinary bladder.

ADRENERGIC BETA RECEPTORSb2 RECEPTORSLocated mainly in the lungs, gastrointestinal tract, liver, uterus, vascular smooth muscle and skeletal muscle.Muscular system:Smooth muscle relaxation Delay in digestion and micturition, inhibition of labour & facilitation of respiration.Blood vessels Dilates arteries increasing perfusion.Circulatory system:Increases cardiac output.Eye: Increases intraocular pressure.GI: Glycogenolysis and gluconeogenesis with Insulin secretion.Lung: Bronchiole dilatation.

ADRENERGIC BETA RECEPTORS3 RECEPTORSLocated mainly in the adipose tissues.Enhancement of lipolysis.Thermogenesis in skeletal muscles.

PHARMACODYNAMICS & PHARMACOKINETICSPHARMACOKINETICS:Most of the drugs are absorbed well orally, peak concentrations occur 1-3 hours after ingestion.Bioavailability of most -blockers is limited.Rapidly distributed.Some like Propranolol and Pindolol are lipophilic and readily cross the blood-brain barrier.Most of them have half-lives in the range of 3-10 hours.

PHARMACODYNAMICSThe effects of -blockers are due to occupation and blockade of receptors. Some actions may be due to partial agonist activity and local anesthetic action.CARDIOVASCULAR SYSTEM:-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. Prominent effect on the heart and valuable in the treatment of angina, chronic heart failure and following myocardial infarction.Negative chronotropic, inotropic, dromotropic & bathmotropic effect.

PHARMACODYNAMICSOppose 2 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 -blockers are advantageous over non-selective ones, however none of them are sufficiently specific to completely avoid 2 -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.Membrane-stabilizing activity.

SPECIFIC AGENTSPROPRANOLOL:Prototypical non-selective b Blocker.METOPROLOL AND ATENOLOL:1-selective group.Preferred in COPD, Asthma (caution), Diabetes and PVD over non-selective -Blockers.NEBIVOLOL:Most highly selective 1-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 rest 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.SOTALOL:Class III Anti-arrhythmic agent.

ADVERSE EFFECTSCARDIAC EFFECTS:Exacerbation of acute heart failure.Negative chronotropic effect.b-Blocker withdrawal.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 USEHypertension.Ischemic heart disease.Cardiac arrhythmias.Heart failure.Glaucoma.Hyperthyroidism.Neurologic diseases.Other cardiovascular diseases: Obstructive cardiomyopathy & Dissecting aortic aneurysm.Miscellaneous: Portal hypertension & Infantile hemangioma.

HISTORYIn the 1960s, Dr. James Black, a Scottish pharmacologist and his associates started working on -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 -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 in 1988.

HISTORYIn 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 quantitative concept of hypertension came along after the discovery of the sphygmomanometer in the early 20th century.Even then, Hypertension was not considered a disease. 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.


TRIALSMRC Trial (1985): Use of Propranolol & Thiazide diuretic to treat mild hypertension. Found decreased risk of Stroke in comparison to placebo.HAPPHY & MAPHY (1987): Use of Atenolol & Metoprolol in comparison to Thiazide diuretics. No significant difference in end-points.STOP Hypertension (1991): Use of Atenolol, Pindolol, Metoprolol & Hydrochlorothiazide. No significant difference observed.SHEP (1991): Use of Atenolol or Hydrochlorothiazide. 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.

TRIALSAASK (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.LIFE (2002): Use of Atenolol and Losartan in patients with hypertension and LVH. Greater reduction in cardiovascular and cerebral end-points with Losartan.INVEST (2003): Comparison of CCB with Atenolol for patients with Hypertension and Coronary Artery Disease. Equally effective.CONVINCE (2003): Use of CCB and Atenolol. No significant difference in risk of MI.


CONCERNSALLHAT (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 [Lindholm et al].Lancet Meta-Analysis (2005): In comparison with other antihypertensive drugs, the effect of blockers is less than optimum, with a raised risk of stroke [Lindholm L et al].Cochrane Meta-Analysis (2012): Beta blockers were inferior to other antihypertensive drugs in reduction of cardiovascular disease [Wiysonge et al].ASCOT-BPLA (2005): CCB and ACEI are better than blocker and Thiazide diuretics [Dahlof B et al].CAFE (2006): Amlodipine reduced central aortic pressure more than Atenolol [Williams B et al].

CONCERNSBased on the mounting evidence, 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 (Peak-trough ratio).Unfavourable metabolic effects.


END OF THE ROAD?A CJC Meta-Analysis in 2014 revealed all blockers were effective in reducing cardiovascular end-points in young adults. Increased incidence of Stroke with Atenolol in older population [Kuyper & Khan].A CMAJ Meta-Analysis in 2007 revealed that most of the previously observed stroke risk was confounded by older populations [Khan & McAlister].Most of the analysis on cardiovascular outcomes are derived from studies using Atenolol.Vasodilatory blockers may be safer!Many recent studies have shown that Nebivolol, Labetalol and Carvedilol significantly reduce central aortic pressure.HJ (2011): Nebivolol vs Metoprolol.JCH (2013): Nebivolol, Carvedilol, Metoprolol.Nature (2014): Losartan vs Carvedilol.HJ (2016): Meta-analysis comparing vasodilating blockers and non-vasodilating blockers.