Drug Induced Arrhythmia Dr. SH TSUI 15 June 2005

ECG Disturbances in Poisoned Patients Fast rate Slow rate Abnormal rhythm/pattern Focus: Underlying mechanism and patho-physiology

Cardiovascular Physiology Electrolyte movement and action potential Phase 0: Na influx Phase 1: Ca Influx Phase 2: Ca influx balanced by outward K current Phase 3: Repolarization Phase 4: Resting state, active ion transport

Action potential of different cardiac muscle cells The depolarizations of SA node and AV node are not dependent on the rapid sodium influx. SA node: spontaneous, slow phase 4 depolarization

Normal Depolarization Calcium induced calcium release from SR.

Normal Repolarization

Cardiovascular Toxicity Mediated by affecting: Calcium channel Sodium channel Potassium channel Na-K-ATPase Pump Electrolyte disturbances Autonomic nervous system

Adrenergic receptors 1 Heart HR, Ionotropy SA/AV conduction 2 Arterioles Relaxation 1 Vasoconstriction 2 CNS  SYM outflow

Drug Induced Tachycardia 1 Enhanced SYM tone Response to increases substrate requirement Tissue hypoxia Hypoglycaemia Increased centrally mediated psychomotor activity CO Salicylates c. Examples: abusive drugs All stimulants

Drug Induced Tachycardia 1 Enhanced SYM tone 2. SYM stimulation Direct central activation Direct peripheral Withdrawal Cocaine Amphetamine Cocaine: Central sympathetic stimulation.  release and  reuptake of catecholamines The first line treatment should be adequate sedation Theophylline: release of endogenous catecholamines with ß-adrenergic receptors stimulation Tachycardia can be treated with cautious use of ß blocker Theophylline

Drug Induced Tachycardia 2 Reflexive Response Response to contractility Response to vasodilatation Response to hypovolaemia TCA Vasodilatation:  Adrenergic blockage (TCA) 2 Adrenergic blockage Fever Salicylates

Drug Induced Tachycardia 3 Parasympathetic antagonism Antagonism of Ach receptors on the myocardium  Release of Ach from the nerve terminal TCA: competitive antagonists of Ach receptors

Drug Induced Tachycardia 4 Enhanced myocardial sensitization  sensitivity to catecholamines Predispose to tachycardia and arrhthymia Halogenated Hydrocarbon Sudden sniffing death syndrome relating to chlorinated hydrocarbon compound

Mnemonics F: A: S: T: Free base or other forms of cocaine Anticholinergics, Antihistamines, Amphetamines, Antipsychotics Sympathomimetics, Solvent abuse Theophylline

Drug Induced Bradycardia 1 Altered autonomic tone Enhanced cholinergic tone Increased central PARA tone Cholinesterase inhibition Central Myocardial muscarinic Ach receptors Organophosphates

Drug Induced Bradycardia 1 Altered autonomic tone Altered SYM tone 1. 2. Clonidine/Imidazolines 3. Depletion of circulating catecholamines Sedative-hypnotic Altered SYM usually causes mild bradycardia 2. Imidazolines are found in eyedrops for vasoconstricitve effects 3. Massive OD of TCA, Anticholinergic and sympathomimetics can cause depletion of NE. Central α2 agonism  SYM output

Drug Induced Bradycardia 1 Reflex response Baroreceptor reflex response to HT PPA PPA: Direct  adrenergic agonist Do not treat reflex bradycardia, treat HT with  antagonist

Drug Induced Bradycardia 2 Toxicity on conduction and pacemakers Mediated by affecting: Na/K ATPase pump Sodium channel ß1 Adrenergic receptor Potassium channel Calcium channel The most profound bradycardias result from overdoses of drugs that have direct effects on the myocardial pacemaker and conduction system cells.

Calcium Channel Blockers Inhibits SA and AV nodal conduction resulting in bradycardia and heart block Slow channel dependent tissues, SA and AV nodes, rely on trans-cellular calcium conductance for action potential generation. CCB: reduce rates of phase 0 depolarization(slow conduction velocities), reduce spontaneous phase 4 depolarization(automaticity), delay recovery of excitability(long refractory period)

CCB Toxicity: Treatments Atropine Calcium Catecholamines Insulin Glucagon Phosphodiesterase inhibitor Atropine: May not be effective in severely poisoned patients Calcium: Increase influx through other calcium channels Increase BP rather than HR Catecholamines: No single agent is consistently effective NE appears to be theoretically appropriate; ß1 adrenergic activity reverses myocardial depressant effect 1 adrenergic effects increases peripheral vascular resistance Insulin: Improves myocardial utilization of carbohydrates Glucagon: No pharmacological advantage over ß adrenergic agonists Phosphodiesterase inhibitors: Inhibit breakdown of cAMP

ß Blockers Toxicity Decrease SA node function Impaired AV conduction Prolonged QRS (Membrane stabilizing activities) Prolonged QT intervals (K channel Blockade)

ß Blockers Toxicity: Treatment Atropine Glucagon Calcium Insulin Catecholamines Phosphodiesterase inhibitor Glucagon: treatment of choice for severe ß antagonist OD Calcium: Increase intracellular Ca, improves BP Insulin: Improves myocardial utilization of carbohydrates Catecholamines: High dose may be required Phosphodiesterase inhibitor: Reduces cAMP breakdown

Mnemonics P: A: C: E: D: Propranolol(ß-blockers), Poppies Anticholinesterase, Aconitine Clonidine, CCB, Ciguatera Ethanol or other alcohols Digoxin Digoxin: Causes AV block by an increase in vagally mediated PARA tone and  in SYM activity

Arrhythmia Underlying mechanisms Increased automaticity Re-entry Triggered automaticity Delayed after depolarization Early after depolarization Increased automaticity: Arises from relatively depolarized level, fast inward Na current is inactivated. Action potential is dependent on the slow inward L-type Ca channel

Automaticity: Digoxin Excessive elevation of the intracellular calcium elevates the resting potential Producing increased automaticity Rhythms due to abnormal automaticity is not overdrive suppressed

Re-entry: Anti-dysrhythmic agents Under normal situations, impulse traveling through both branches in the antegrade directions, meet and annihilate each other. 2. Impulse in branch 1 is blocked. 3. Impulse in branch 2 can enter branch 1 in the retrograde direction. Re-entry mechanisms appear to be responsible to most of the dysrhythmias attributable to anti-dysrhythmiic agents

TCA Terminal right axis deviation RBB is preferentially affected Appearance of right ventricular force at the late phase of QRS

Predictive Values QRS duration Seizures: 0% if <100ms, 30% if >100ms Ventricular dysrhythmias: 0% if <160ms, 50% if >160ms Boehnert M, N Eng J Med 1985 313;474-479

Predictive Values Amplitude of terminal R wave in aVR: RaVR 3mm predicts seizures and dysrhythmia Liebelt EL Ann Emerg Med 1995;26:195-201 Terminal R-axis deviation, prolonged QTc, sinus tachycardia: specific and sensitive for TCA OD Wolfe TR Ann Emerg Med 1989;18:348-351

TCA: tachyarrhythmia VT Mechanisms Non-uniform conduction slowing  Re-entry Precipitated by hypoxia, tissue ischaemia and metabolic acidosis Sinus tachycardia plus aberrancy is more common

Delayed After-depolarization Normal depolarization is followed by an oscillation during phase 4 Occurs with  intracellular Ca E.g. Cardiac glycoside toxicity Triggered rhythms: is an abnormality of impulse generation in which pulses are initiated by oscillations in membrane potential which arise following the upstroke of a preceding action potential. DAD occurs after the completion of re-polarization. DAD amplitude increases with increased HR and pacing

Digoxin Toxicity: Risks of treatment Pacing: DAD amplitude Overdrive supression: Useless in dysrhythmias due to automaticity DC version: Risk of inducing VF/VT Treatment choices: Atropine, Lignocaine, Phenytoin, Amiodarone *Digoxin antibody

Early After-depolarization Occurs during the downslope of phase 3 of the action potential Occurs when cardiac action potential is markedly prolonged ( QTc)

Drugs that cause QT prolongation

Aconitine Toxicity  Na influx through Na channel Delay the final phase of repolarization and promote premature excitation Expect Na channel blockers to be effective Amiodarone, flecainide, procainamide have been reported to be successful in terminating ventricular dysrhthymias Aconitine toxicity commonly presents initially as bradycardia (muscarinic effect)

Treatment of Drug-induced ventricular dysrhythmias NaHCO3 if widened QRS Lignocaine for prolonged QT Mg, DC version, Overdrive pacing for Torsades de pointes, correct e-

Toxin Induced SVT Usually mediated by sympathomimetic activity of drugs Cardioversion Adenosine: may not be effective for methylxanthines toxicity CCB and ß-blockers: risks Toxin removal Treat dysrhythmia if it cause haemodynamic instability Problem of recurrence Benzo can be used to abate CNS stimulation

Conclusion Understanding the underlying patho-physiology of toxin induced arrhythmias improves our diagnosis and treatment of such problems