1. Drug Induced Arrhythmia
Dr. SH TSUI
15 June 2005

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

3. 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

4. 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

5. Normal Depolarization
Calcium induced calcium release from SR.

6. Normal Repolarization

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

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

9. 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

10. 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

11. 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

12. 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

13. 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

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

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

16. 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

17. 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

18. 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.

19. 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)

20. 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

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

22. 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

23. 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

24. 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

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

26. 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

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

28. 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 ;

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

30. 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

31. 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

32. 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

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

34. Drugs that cause QT prolongation

35. 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)

36. 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-

37. 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

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