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Chapter: Modern Medical Toxicology: Cardiovascular Poisons: Diurets, Antihypertensives and Antiarrhythmics

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Beta Adrenergic Antagonists (Beta Blockers) - Sympatholytic Drug Cardiovascular Poison

Beta-adrenergic blocking agents compete with endogenous and/or exogenous beta-adrenergic agonists for receptor sites.

Beta Adrenergic Antagonists (Beta Blockers)

Beta-adrenergic blocking agents compete with endogenous and/or exogenous beta-adrenergic agonists for receptor sites. Depending upon the agent and its relative selectivity for beta1 (located primarily in the heart) and beta2 receptors (located chiefly in bronchial smooth muscle and blood vessels), principal pharmacologic effects include a lowering of blood pressure, negative inotropic and chronotropic effects, and depressed AV conduction.

Examples

Acebutolol, adimolol, alprenolol, amosulalol, arotinolol, atenolol, befunolol, betaxolol, bevantolol, bisoprolol, bopindolol, bucindolol, bufetolol, bufuralol, bunitrolol, bupran-olol, butofilolol, carazolol, carteolol, carvediolol, celiprolol, cetamolol, coloranolol, cycloprolol, dilevalol, divelalol, draquinolol, esmolol, espanolol, flestolol, indenolol, labetalol, landiolol, levobetaxolol, levobunolol, levomoprolol, medrox-alol, mepindolol, metipranolol, metoprolol, nadolol, nebivolol, nifenalol, nipradilol, oxprenolol, penbutolol, pindolol, prac-tolol, propranolol, sotalol, teratolol, tilisolol, and timolol.

First generation beta blockers (nadolol, propranolol, pind-olol, labetalol, sotalol, timolol, etc.) are antagonists at both beta1 and beta2 adrenoceptors and are known to aggravate asthma, obstructive airway disease, peripheral artery disease, and diabetes mellitus. Second generation drugs such as acebutolol, atenolol, and metoprolol are selective for beta1 adrenoceptors, and therefore relatively safer. Recently, a new beta-adrenergic receptor referred to as beta3 adrenoceptor has been discovered. Classic beta blockers are all agonists (not antagonists) at this receptor.*

Uses

Beta-blockers are used in the treatment of hypertension, angina, arrhythmias, cardiomyopathy, migraine headaches, and thyro-toxicosis. Ophthalmic products are used in the treatment of glaucoma.

Adverse Effects

·      Bradycardia, dizziness, fatigue, diarrhoea, sleepiness, confusion, depression, and headache. While CNS effects at therapeutic doses are more often associated with more lipid soluble agents (propranolol, metoprolol), in overdose all agents may cause significant CNS depression. Effects range from drowsiness and lethargy to obtundation and coma. Therapeutic doses of beta adrenergic blocking agents may cause bronchospasm in susceptible patients. Worsening angina may develop in patients after withdrawal from chronic beta blocker therapy.

·      Drug-induced retroperitoneal fibrosis has been reported following treatment with practolol, atenolol, and oxpre-nolol.

·              Propranolol can cause hypoglycaemia and resultant seizures in diabetics treated with oral hypoglycaemics or insulin and in non-diabetics who are dieting, fasting and exercising. The clinical effects of hypoglycaemia (tachy-cardia and sweating) may be absent due to beta-blockade in such cases.

·              Propranolol appears to cross the placenta and may result in intrauterine growth retardation, bradycardia, hypogly-caemia, respiratory depression and impaired response to anoxic stress. Acebutolol, atenolol, betaxolol, labetalol, metoprolol, nadolol, propranolol and timolol are excreted in human breast milk.

Drug Interactions

·              Severe bradycardia, conduction blocks and hypotension have been reported in patients taking calcium antagonists and beta blockers at therapeutic doses.

·              Complete atrioventricular block, bradycardia, hypotension and biventricular failure have been reported after thera- peutic use of digoxin and propranolol.

·              Quinidine inhibits metabolism of timolol and increases the degree of beta blockade experienced after use of timolol eye drops.

·              Dystonia may develop if propranolol and gabapentin are given together, due to synergistic effect.

Clinical (Toxic) Features

·      Lipid soluble beta blockers such as propranolol, oxprenolol, labetalol, metoprolol, pindolol, and timolol are capable of producing serious toxicity. Fatalities have been reported with propranolol, metoprolol, acebutolol, and oxprenolol. Co-ingestion of alcohol is nearly always catastrophic. Labetalol and atenolol are said to be safest in overdose and rarely cause death.

·      Manifestations of overdose include hypotension, brady-cardia, arrhythmias, delirium, seizures, mydriasis, coma, and respiratory failure. Hypoglycaemia is common in chil-dren. Bradycardia and hypotension are the most common effects in beta blocker overdose. Complications of profound hypotension may include acute renal failure, respiratory failure and non-cardiogenic pulmonary oedema.

·      Other cardiovascular effects may include atrioventricular blocks, intraventricular conduction delays, ventricular arrhythmias, pulmonary oedema and cardiac arrest. An irregular pulse may be a sign of conduction defects or arrhythmias. Asystole has also been reported.

·      Pindolol has greater beta-agonist properties and overdoses have been associated with hypertension and tachycardia.

·      CNS depression is common in patients with significant cardiovascular toxicity. Seizures have been frequently reported with propranolol overdose. Sotalol is notorious for causing delayed toxicity, and for inducing a prolonged QT interval and ventricular arrhythmias. Fatalities are common.

·      Metabolic acidosis may develop in patients with profound hypotension or seizures.

·      Ophthalmic preparations containing beta-blockers may cause systemic manifestations. Increased airway resistance (usually in asthmatics), hypoglycaemia, fatigue, behav-ioural abnormalities, and diplopia may be noted.

·              Abrupt stoppage of beta blockers after chronic use may result in rebound hypertension, tachycardia, palpitations, tremor, headache, and sweating. Patients with angina may develop myocardial infarction.

Diagnosis

Plasma levels of these agents are not clinically useful and are not routinely available.

Treatment

•      Outlined in Table 22.1.


•      Glucagon is said to have antidotal action. It produces a positive chronotropic and inotropic cardiac effect, which occurs despite beta-blockage. The drug has been reported to increase myocardial contractility in patients refractive to isoproterenol. Glucagon is thought to activate the adenylate cyclase system at a different site than isoproterenol. If the patient responds at a particular dose of glucagon, start an hourly infusion at the response dose (e.g. if a patient responds to 10 mg, then start an infusion at 10 mg per hour).

•      Monitor electrolytes and renal function in patients with hypotension.

•      Monitor blood glucose in symptomatic children and diabetics.

•      Institute continuous cardiac monitoring, monitor blood pressure, and obtain an ECG.

•      Obtain a chest X-ray in patients with respiratory depression, significant hypotension or evidence of pulmonary oedema.

•      Patients, who at presentation show evidence of significant cardiovascular (bradycardia, heart failure, heart block, hypotension, electromechanical dissociation, asystole, new bundle branch block or widened QRS complex) respiratory (respiratory depression, bronchospasm, or pulmonary oedema) or neurologic toxicity (CNS depres- sion or seizures), independent of the dose ingested, should be admitted to a monitored setting for at least 24 hours of observation and treatment.

•      Hypotension usually responds to intravenous glucagon, atropine, isoproterenol or pacing. Atropine reduces vagal stimulation and subsequently increases heart rate. Isoproterenol is a beta agonist which competitively antagonises the effect of the beta-blocker. It is used for temporary control of haemodynamically signifi-cant bradycardia; generally other modalities (atropine, dobutamine, pacing) should be used first because of the tendency to develop ischaemia and arrhythmias with isoproterenol. 1 mg of isoproterenol is added to 250 ml of dextrose 5% in water, for a final concentration of 4 mcg/ml. Infuse 2 mcg/min, gradually titrating to 10 mcg/min as needed, to desired response. If hypotension persists, administer dopamine or noradrenaline. Refrac-tory cardiotoxicity may respond to calcium chloride. Intra-aortic balloon pump has been used successfully after pharmacologic therapy failed, in cases of severe propranolol and atenolol poisoning.

•      Extracorporeal membrane oxygenation may be useful in providing haemodynamic support for arrhythmias, hypotension, and heart failure unresponsive to glucagon, dopamine, noradrenaline, adrenaline, or pacemaker.

•      Hypoglycaemia should be managed with intravenous dextrose. Bronchospasm responds to salbutamol (0.25 to 0.5 ml in 2 to 4.5 ml of normal saline delivered every 4 to 6 hours per nebuliser).

•      Nadolol, sotalol, acebutolol, and atenolol are haemodi-alysable. Propranolol, metoprolol, and timolol are not removed by haemodialysis. Haemoperfusion is said to be effective in nadolol, atenolol, and sotalol overdose. However, it should be considered only when treatment with glucagon and other pharmacotherapy fails.

 

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