Antiarrhythmic Drugs Toxicity Presentation PDF

Antiarrhythmic drugs toxicity By pharmacist Noor alzahra Hussein fadel  Introduction Cardiac arrhythmia Are abnormalities in the rate, regularity or site of origin of cardiac impulse,or disturbance in conduction of the impulse such that normal sequence of activation of the atri...

Antiarrhythmic drugs toxicity By pharmacist Noor alzahra Hussein fadel  Introduction Cardiac arrhythmia Are abnormalities in the rate, regularity or site of origin of cardiac impulse,or disturbance in conduction of the impulse such that normal sequence of activation of the atria and ventricles is altered.which requires administration of one of the antiarrhythmic drugs.Arrhythmias may occurs as result of heart disease or from a disorder that affects cardiovascular function conditions such as emotional stress , hypoxia , electrolytes imbalance also may trigger arrhythmia. Arrhythmia is result from : 1- disturbance in impulse formation 2-distrubance in impluse conduction 3-both  Cardiac Electrophysiology The heart contain specialized tissue that exhibit automaticity (can generate A.P. in the absence of external stimut). These peacemaker cells differs from other myocardial cells in showing a slow spontaneous depolarization during diastole (phase 4) caused by the inward current carried by sodium and calcium The depolarization is fastest in the SA node (normal pacemaker )beating at frequency 60- 100 beat/min then impulse spreads rapidly to the atria and enters the AV node (which is normally the only conductive pathway between the atria and ventricles ). Classification of antiarrhythmic drugs dependent on predominant effects on action potential Class I (Na channel blockers ) -IA (Na channle blocked ,prolonged repolarization)ex : procainamid, quindine ,disopyramide IB-( Na channel blocked, shortened repolarization) ex: lidocaine, mexiletine, phenytoin. IC-(Na channel blocked, repolarization unchanged) Ex: flecainide , propafenone Class II Beta blocker drugs (propanolol, metoprolol , esmolol) Class III potassium channels blocker (amiodarone, bretylium , sotalol) Class IV calcium channels blocker (diltiazem, verapamil(. Mechanism of toxicity Class l drugs Act by inhibiting the fast sodium channel responsible for initial cardiac cell depolarization and impulse conduction In overdose, all class l drugs have the potential to marked depress myocardial automaticity, conduction, and contractility. Type la inhibit the outward potassium channel , delaying repolarization, and resulting in a prolonged QT interval that may be associated with polymorphic ventricular tachycardia (torsade de pointes ) Quinidine and disopyramide also have anticholinergic activity and quindine has alpha adrenergic blocker activity Class ll act by slow down for heart rate by blocking sympathetic hormones such as adrenaline and noradrenaline. Class lll: act primarily by blocking potassium channel to prolong the duration of the action potential and the effective refractory period, resulting in QT interval prolongation at therapeutic doses Amiodarone is also a non competitive beta adrenergic blockers and has sodium channels and calcium channels blocking effects , which may explain its tendency to causes bradyarrhythmias. Amiodarone may also release iodine, and chronic use has resulted in altered thyroid function Dronedarone is an analog of amiodarone but doesn't contain iodine and doesn't affect thyroid function. IV administration of bretylium inhibition of neurotransmitter release from sympathetic nerves ending. Class lV: decreasing the inward current carried by calcium, they slow conduction and prolong the effective refractory period in the AV nod. Toxic dose In general, those drugs Have a narrow therapeutic index, and sever toxicity may occur slightly above or sometimes even within the therapeutic range, especially if two or more antiarrhythmic drugs are taken together Ingestion of twice the daily therapeutic dose should be considered potentially life threatening. Clinical presentation Class l drugs cardiotoxic effects , including -sinus bradycardia, sinus nod arrest or asystole -QRS or QT interval prolongation -Decreased myocardial contractility, Which, along with alpha adrenergic or ganglionic blocked, my result in hypotension -Sinus tachycardia (caused by anticholinergic effects ) Torsades de pointes and fatal ventricular fibrillations CNS toxicity presents as coma, respiratory depression, and seizures Quinidine commonly causes Nausea, vomiting,and diarrhea after acute ingestion With chronic doses cinchonism , a collection of symptoms that includes headache, deafness, tinnitus , vertigo , and blurred vision. Procainamid may cause with chronic therapy a lupus like syndrome ( arthralgias , fever, myocarditis) Disopyramide and quinidine can causes anticholinergic effects such as Glaucoma, constipation, dry mouth, dilated pupils , and urinary retention Lidocaine can causes methemoglobinemia. Class lll Bretylium The major toxic side effects is hypotension caused by inhibition of catecholamines release. Orthostatic hypotension may persist for several hours. After rapid IV injection, transient hypertension, Nausea, and vomiting may occur. Amiodarone -bradyarrhythmias , hypotension, and asystole have been associated with lV loading.Acute hepatitis and acute pneumonia have rarely been associated with lV loading doses given over several days.  With chronic use Amiodarone may cause -ventricular arrhythmia or bradyarrhythmias (sinus arrest , AV block) The most important lif threatening toxicity from amiodarone is pulmonary toxicity (pneumonitis) which has a fatality rate of 10% - hepatitis - photosensitivity - dermatitis - corneal deposit - hypothyroidism or hyperthyroidism -tremor and peripheral neuropathy - mild elevation in liver enzymes is common sever liver toxicity is rare Chronic dronedarone use doubles the risk of death in patients with symptomatic heart failure, its also contraindications in patients with Permanent atrial fibrillations Chronic dofetilide use has been associated with QT prolongation and torsades de pointes particularly in people whose renal dysfunction or who taking other QT prolonging drugs , and with the development of hypokalemia and hypomagnesemia. Diagnosis _The most important diagnostic test for patients with acute antiarrhythmic toxicity is electrocardiography _ serum electrolytes should be obtained _Chest radiographs it should be obtained in patients taking amiodarone and presenting with pulmonary symptoms _Thyroid function tests should be obtained in patients taking amiodarone who present with signs and symptoms of hypothyroidism or hyperthyroidism. Treatment In patients with intoxication by class la or class l drug , QRS prolongation, bradyarrhythmias, and hypotension may respond to sodium bicarbonate Sodium bicarbonate reverses cardiac depressant effects caused by inhibition of the fast sodium channels. It has beneficial effects by increasing the Serum sodium level to help offset the sodium channels antagonism by prevent penetration toxic substance to tissue by increasing Serum protein binding (decreased free drug ) in a more alkalotic serum and increase urinary execration Torsades de pointes should be treated with lV magnesium, repletion of potassium. Decontamination Activated charcoal, gastric lavage Enhanced elimination Owing to extensive tissue binding with resulting large volumes of distribution, dialysis and hemoperfusion are not likely to be effective for most of these agents. Disopyramide and procainamid have smaller volume distribution and can be removed by dialysis