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Beta-blockers Dr.Md.Toufiqur Rahman FCPS, MD, FACC, FESC, FRCPE, FSCAI, MBBS, FAHA, FSCAI, FCCP, FRCPG Associate Professor of cardiology NICVD, Dhaka

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Introduction and history Beta blockers (sometimes written as ?-blockers) or beta-adrenergic blocking agents, beta-adrenergic antagonists, or beta antagonists, are a class of drugs used for various indications, but particularly for the management of cardiac arrhythmias, cardioprotection after myocardial infarction (heart attack), and hypertension As beta adrenergic receptor antagonists, they diminish the effects of epinephrine (adrenaline) and other stress hormones. In 1958 the first beta blocker, dichloroisoproterenol, was synthesised by Eli Lilly Laboratories, but it was Sir James W. Black in 1962, who found the first clinically significant use of beta blockers with propranolol and pronethalol; it revolutionized the medical management of angina pectoris and is considered by many to be one of the most important contributions to clinical medicine and pharmacology of the 20th century.

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Introduction Beta blockers block the action of endogenous catecholamines (epinephrine (adrenaline) and norepinephrine (noradrenaline) in particular), on ?-adrenergic receptors, part of the sympathetic nervous system which mediates the "fight or flight" response. There are three known types of beta receptor, designated ?1, ?2 and ?3 receptors. ?1-adrenergic receptors are located mainly in the heart and in the kidneys. ?2-adrenergic receptors are located mainly in the lungs, gastrointestinal tract, liver, uterus, vascular smooth muscle, and skeletal muscle.?3-adrenergic receptors are located in fat cells.

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Indications for beta blockers Angina pectoris Atrial fibrillation Cardiac arrhythmia Congestive heart failure Essential tremor Glaucoma Hypertension Migraine prophylaxis Mitral valve prolapse Myocardial infarction Phaeochromocytoma, in conjunction with ?-blocker Symptomatic control (tachycardia, tremor) in anxiety and hyperthyroidism

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Beta blockers have also been used in the following conditions Acute aortic dissection Hypertrophic obstructive cardiomyopathy Marfan syndrome (treatment with propranolol slows progression of aortic dilation and its complications) Prevention of variceal bleeding in portal hypertension Possible mitigation of hyperhidrosis Social anxiety disorder and other anxiety disorders

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Adverse effects Adverse drug reactions(ADRs) associated with the use of beta blockers include: nausea, diarrhoea, bronchospasm, dyspnea, cold extremities, exacerbation of Raynaud's syndrome, bradycardia, hypotension, heart failure, heart block, fatigue, dizziness, alopecia (hair loss), abnormal vision, hallucinations, insomnia, nightmares, sexual dysfunction, erectile dysfunction and/or alteration of glucose and lipid metabolism. Mixed ?1/?-antagonist therapy is also commonly associated with orthostatic hypotension. Carvedilol therapy is commonly associated with edema. Central nervous system (CNS) adverse effects (hallucinations, insomnia, nightmares) are more common in agents with greater lipid solubility, which are able to cross the blood-brain barrier into the CNS. Similarly, CNS adverse effects are less common in agents with greater aqueous solubility.

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Adverse effects associated with ?2-adrenergic receptor antagonist activity (bronchospasm, peripheral vasoconstriction, alteration of glucose and lipid metabolism) are less common with ?1-selective (often termed "cardioselective") agents, however receptor selectivity diminishes at higher doses. Beta blockade, especially of the beta-1 receptor at the macula densa inhibits renin release, thus decreasing the release of aldosterone. This causes hyponatremia and hyperkalemia. A 2007 study revealed that diuretics and beta-blockers used for hypertension increase a patient's risk of developing diabetes while ACE inhibitors and Angiotensin II receptor antagonists (Angiotensin Receptor Blockers) actually decrease the risk of diabetes. Clinical guidelines in Great Britain, but not in the United States, call for avoiding diuretics and beta-blockers as first-line treatment of hypertension due to the risk of diabetes. Adverse effects

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Precautions Beta blockers must not be used in the treatment of cocaine, amphetamine, or other alpha adrenergic stimulant overdose. The blockade of only beta receptors increases hypertension, reduces coronary blood flow, left ventricular function, and cardiac output and tissue perfusion by means of leaving the alpha adrenergic system stimulation unopposed. The appropriate antihypertensive drugs to administer during hypertensive crisis resulting from stimulant abuse are vasodilators like nitroglycerin, diuretics like furosemide and alpha blockers like phentolamine.

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Toxicity Glucagon has been used in the treatment of overdose. Glucagon has a positive inotropic action on the heart and decreases renal vascular resistance. It is therefore useful in patients with beta-blocker cardiotoxicity. Cardiac pacing should be reserved for patients unresponsive to pharmacological therapy. Patients who experience bronchospasm due to the B2 blocking effects of non-selective beta-blockers may be treated with anticholinergic drugs such as Ipratropium, which are safer than beta agonists in patients with cardiovascular disease.

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?-Receptor antagonism Stimulation of ?1 receptors by epinephrine induces a positive chronotropic and inotropic effect on the heart and increases cardiac conduction velocity and automaticity.Stimulation of ?1 receptors on the kidney causes renin release. Stimulation of ?2 receptors induces smooth muscle relaxation, induces tremor in skeletal muscle, and increases glycogenolysis in the liver and skeletal muscle. Stimulation of ?3 receptors induces lipolysis. Beta blockers inhibit these normal epinephrine-mediated sympathetic actions,but have minimal effect on resting subjects. That is, they reduce excitement/physical exertion on heart rate and force of contraction, and also tremor and breakdown of glycogen, but increase dilation of blood vessels and constriction of bronchi. It is therefore expected that non-selective beta blockers have an antihypertensive effect. The primary antihypertensive mechanism of betablockers is unclear but it may involve reduction in cardiac output (due to negative chronotropic and inotropic effects). It may also be due to reduction in renin release from the kidneys, and a central nervous system effect to reduce sympathetic activity (for those ?-blockers that do cross the blood-brain barrier, e.g. Propranolol).

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?-Receptor antagonism Antianginal effects result from negative chronotropic and inotropic effects, which decrease cardiac workload and oxygen demand. Negative chronotropic properties of beta blockers allow the lifesaving property of heart rate control. Beta blockers are readily titrated to optimal rate control in many pathologic states. The antiarrhythmic effects of beta blockers arise from sympathetic nervous system blockade – resulting in depression of sinus node function and atrioventricular node conduction, and prolonged atrial refractory periods. Sotalol, in particular, has additional antiarrhythmic properties and prolongs action potential duration through potassium channel blockade. Blockade of the sympathetic nervous system on renin release leads to reduced aldosterone via the renin angiotensin aldosterone system with a resultant decrease in blood pressure due to decreased sodium and water retention.

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Intrinsic sympathomimetic activity Also referred to as intrinsic sympathomimetic effect, this term is used particularly with beta blockers that can show both agonism and antagonism at a given beta receptor, depending on the concentration of the agent (beta blocker) and the concentration of the antagonized agent (usually an endogenous compound such as norepinephrine. Some beta blockers (e.g. oxprenolol, pindolol, penbutolol and acebutolol) exhibit intrinsic sympathomimetic activity (ISA). These agents are capable of exerting low level agonist activity at the ?-adrenergic receptor while simultaneously acting as a receptor site antagonist. These agents, therefore, may be useful in individuals exhibiting excessive bradycardia with sustained beta blocker therapy. Agents with ISA are not used in post-myocardial infarction as they have not been demonstrated to be beneficial. They may also be less effective than other beta blockers in the management of angina and tachyarrhythmia.

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Effects of beta blockers ?1-Receptor antagonism Some beta blockers (e.g. labetalol and carvedilol) exhibit mixed antagonism of both ?- and ?1-adrenergic receptors, which provides additional arteriolar vasodilating action. Other effects Beta blockers decrease nocturnal melatonin release, perhaps partly accounting for sleep disturbance caused by some agents. They can also be used to treat glaucoma because they decrease intraocular pressure by lowering aqueous humor secretion.

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Non-selective agents Alprenolol Bucindolol Carteolol Carvedilol (has additional ?-blocking activity) Labetalol (has additional ?-blocking activity) Nadolol Penbutolol(has intrinsic sympathomimetic activity) Pindolol (has intrinsic sympathomimetic activity) Propranolol Sotalol Timolol Eucommia bark (herb)

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?1-Selective agents Acebutolol (has intrinsic sympathomimetic activity) Atenolol Betaxolol Bisoprolol Celiprolol Esmolol Metoprolol Nebivolol

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?2-Selective agents Butaxamine (weak ?-adrenergic agonist activity) - No common clinical applications, but used in experiments. ICI-118,551 Highly selective ?2-adrenergic receptor antagonist - No known clinical applications, but used in experiments due to its strong receptor specificity. ?3-Selective agents SR 59230A (has additional ?-blocking activity) - Used in experiments

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Indication differences Agents specifically indicated for cardiac arrhythmia Esmolol, sotalol, landiolol Agents specifically indicated for congestive heart failure Bisoprolol, carvedilol, sustained-release metoprolol, nebivolol Agents specifically indicated for glaucoma Betaxolol, carteolol, levobunolol, metipranolol, timolol Agents specifically indicated for myocardial infarction Atenolol, metoprolol, propranolol Agents specifically indicated for migraine prophylaxis Timolol, propranolol Propranolol is the only agent indicated for control of tremor, portal hypertension, and esophageal variceal bleeding, and used in conjunction with ?-blocker therapy in phaeochromocytoma.

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Pharmacological classification of beta-blockers

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Effects mediated by beta- receptors

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Intravenous dosing of beta-blockers

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Use of beta-blockers in AMI

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Use of beta-blockers in secondary prevention after myocardial infarction

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Use of beta-blockers in non-ST segment elevation ACS

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Use of beta-blockers in chronic,stable ischemic heart disease

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Use of beta-blockers in chronic heart failure

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Practical guidance on using b-adrenergic blockers in heart failure

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Practical guidance on using b-adrenergic blockers in heart failure

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Use of beta-blockers in arrhythmia Eur Heart J 2001;1852–923. Eur Heart J 2003;24:1857–97. Eur Heart J 2003;24:28–66. Eur Heart J 2001;22:1374–450.

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Use of beta-blockers in prevention of sudden cardiac death Eur Heart J 2003;24:28–66. Eur Heart J 2001;22:1374–450. Eur Heart J 2003;24:13–5.

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Use of beta-blockers in hypertension Eur. Heart J. 1998;19:1434–1503. Circulation 1999;100:1134–46. Circulation 2001;104:1577–9. J Hypertens 1999;17:151–8.

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Use of beta-blockers in aortic dissection Eur Heart J 2001;22:1642–81.

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Use of beta-blockers in non-cardiac surgery Circulation 2002;105:1257–67.

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Classes of Recommendations

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Levels of Evidence

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