1. October 6, 2006 Frank F. Vincenzi
Antiarrhythmic Drugs
October 6, 2006
Frank F. Vincenzi

2. Antiarrhythmic drug list
adenosine (Adenocard®)
amiodarone (Cordarone®)
atropine
bretylium (Bretylol®)
digoxin (Lanoxin®)
diltiazem (Cardizem®)
isoproterenol (Isuprel®)
lidocaine (Xylocaine®)
procainamide (Pronestyl®)
propranolol (Inderal®)
quinidine (Quinidex®)
verapamil (Calan®, Isoptin®)

3. Fundamental features of cardiac excitation
Automaticity capacity for self excitation
Excitability ability to respond to stimuli and conduct action potentials Refractory period time following excitation during which a second action potential can not be elicited and conducted Membrane responsiveness relationship between membrane activation voltage and the maximal rate of rise of the action potential

4. Excitable tissues in heart
Slow response tissues (mainly Ca channels) SA node AV node
Fast response tissues (mainly Na channels) atrium ventricle bundle of His Purkinje fibers

5. Typical action potential in SA nodal cells

6. Typical action potential in AV nodal cells

7. Typical action potential in cardiac muscle cells

8. Influence of diastolic membrane potential on action potential upstroke rate in a given cell: ‘Membrane Responsiveness’

9. Treatment for bradyarrhythmias
Atropine prevents vagally-induced inhibition of supraventricular pacemakers and vagally induced inhibition of AV nodal conduction
Isoproterenol increases automaticity of all parts of the heart and promotes AV nodal conduction
Artificial pacemaker - transvenous or or implantable

10. Treatment for tachyarrhythmias
Decrease automaticity of ectopic pacemakers (e.g., reflex activation of vagus, adenosine, quinidine, beta blockers, Ca channel blockers)
Prevent re-entry excitation (lidocaine, amiodarone, quinidine, etc.)
Partially block AV nodal conduction of supraventricular arrhythmias (digitalis, beta-blockers, Ca channel blockers)

11. Agents which partially block AV nodal conduction may be useful in the treatment of supraventricular tachyarrhythmias
Digitalis - by increasing vagal tone increases AV nodal refractory period
Beta blockers - by preventing sympathetically mediated increases in AV nodal conduction slow or block conduction, also depress catecholamine augmented automaticity
Ca channel blockers - by inhibiting Ca channels depress AV nodal conduction velocity and increase refractory period, also suppress automaticity

12. adenosine (unclassified)(suppresses automaticity)
Metabolite of ATP, etc., released in heart under conditions of ischemia (rapidly causes vasodilation)
Increases potassium conductance and inhibits cAMP mediated increase in calcium influx
Useful in the acute treatment of supraventricular tachyarrhythmias
Extremely short half life, used IV only
(also used as a test for coronary dilation)

13. Vaughan Williams Classification of Antiarrhythmic Drugs
I. Drugs with direct membrane action (e.g., Na channel blockade A. moderate phase 0 depression B. minimal phase 0 depression, usually shorten repolarization C. marked phase 0 depression, little effect on repolarization
II. Sympatholytic drugs
III. Drugs that prolong repolarization
IV. Calcium channel blockers
For a less arbitrary classification based on arrhythmogenic mechanisms and potentially vulnerable parameters, see the report of the Task Force of the Working Group on Antiarrhythmias of the European Society of Cardiology, Circulation 84: , 1991

14. Examples of Antiarrhythmic Drugs According to the Vaughan Williams Classification
Class I A - quinidine, procainamide B - lidocaine C - (encainide, flecainide)
Class II - propranolol
Class III - amiodarone, bretylium
Class IV - verapamil, diltiazem

15. Antiarrhythmic drugs: a common theme
Effective antiarrhythmic drugs increase the refractory period compared to action potential duration: ERP/APD
Relatively speaking, this gives ‘more time’ for recovery of membrane potential and makes slow conduction less likely. Slow conduction is a formula for disaster.

16. quinidine (Class IA) (moderate inhibition of Na channels)
Generally useful in supraventricular arrhythmias (decreases automaticity, increases refractory period)
Atropine-like properties (may promote AV conduction - paradoxical tachycardia)
Mild adrenergic blockade (hypotension)
High doses promote bizarre cardiac arrhythmias, torsades des pointes
Cinchonism GI upset, tinnitus, loss of hearing, blurred vision, headache, diplopia, delerium, psychosis, rarely thrombocytopenia

17. Quinidine decreases membrane responsiveness (moderate inhibition of Na channels)

18. Membrane Responsiveness: Relation between membrane activation voltage and max dV/dt

19. procainamide (Class IA) (moderate inhibition of Na channels)
Generally useful in ventricular arrhythmias
Little or no atropine-like properties
Cardiac toxicity, hypotension, CNS effects, rarely agranulocytosis or systemic lupus erythematosus (SLE)-like syndrome

20. lidocaine (class IB) (minor inhibition of [normal] Na channels)
Useful mainly in ventricular arrhythmias
Minor effects on normal automaticity or membrane responsiveness, greatly suppresses membrane responsiveness in ‘sick’ fibers (by binding to inactive Na channels)
Major toxicity in CNS; disorientation, convulsions, respiratory arrest

21. Lidocaine decreases membrane responsiveness (selective inhibition of Na channels in depolarized cells)
Lidocaine

22. Class IC antiarrhythmics (major inhibition of Na channels)
Flecainide for prevention of paroxysmal atrial fibrillation (PAF) and paroxysmal supraventricular tachycardia (PSVT) prevention and ventricular arrhythmias.
Flecainide and encainide (off market?) were associated with increased mortality CAST, Cardiac Arrhythmia Suppression Trial Echt et al., Mortality and morbidity in patients receiving encainide, flecainide, or placebo, New Engl. J. Med. 324: , 1991.

23. Class IC antiarrhythmics: major inhibition of membrane responsiveness (major inhibition of Na channels)
Flecainide or encainide

24. beta-blockers (class II)
Decrease cardiac automaticity and contractility, partly by blocking beta-adrenergic receptors (& partly by direct effects on cardiac cell membranes). Antagonize the effects of catecholamines on Ca channels (reduce automaticity and slow conduction in partially depolarized cells and decrease myocardial contractility)
Useful in supraventricular arrhythmias
Increase effective refractory period of AV node
AV block, asystole, sudden withdrawal can precipitate angina, arrhythmias or myocardial infarction
Contraindicated in asthma (relatively for beta-1 selective), may mask tachycardia of hypoglycemia, CNS effects

25. amiodarone (Class III) (but also has Class I, II and IV effects)
A ‘dirty drug’, inhibits K channels, (delays repolarization), Na channels and Ca channels (slight), blocks beta-receptors non-competitively, blocks alpha receptors, potent suppressor of ectopic automaticity (only rarely causes torsades des pointes), and some vagolytic effects.
Approved for ventricular tachycardia, ventricular fibrillation and paroxysmal supraventricular tachycardia, used in other arrhythmias as well; has anti-anginal properties
Adverse reactions (too many to list) occur in about 70% of patients, sufficient to cause discontinuation in 5-20%.
Extremely long, biphasic, half life (initial about 10 days, terminal about 50 days), metabolized in liver, Vd ~ 70 l/kg

26. Amiodarone: selected adverse reactions (far too many to list)
ARDS
Ataxia
AV block
Bronchiolitis obliterans
Dyspnea
Epididymitis
Heart failure
Hepatitis
Hyper/hypothyroidism
Macular degeneration
Optic neuritis
Pancreatitis
Peripheral neuropathy
Pneumonitis
QT prolongation
Sinus bradycardia
Thrombocytopenia
Torsade de pointes
Toxic epidermal necrolysis
Vasculitis

27. Amiodarone in out-of-hospital Resuscitation of REfractory sustained ventricular Tachyarrhythmias (ARREST) (504 pts, out of hospital arrest, >= 3 precordial shocks, 1 mg EPI, IV then:
Kudenchek et al., NEJM 341: , 1999

28. bretylium (class III)
Effects on cardiac (ventricle >> atrium) cell membranes in addition to its effects on adrenergic nerve terminals
Useful in drug resistant ventricular fibrillation (with cardioversion) or sustained ventricular tachycardia in intensive care situations
Classified as an agent that prolongs action potential duration; actually increases ERP more than APD

29. verapamil (class IV) Blocks mainly L-type calcium channels
Decreases SA and Purkinje fiber automaticity, slows conduction through and increases refractory period of AV node
Useful mainly in supraventricular arrhythmias or ventricular arrhythmias caused by coronary spasm
GI disturbances, cardiac toxicity including heart failure, AV block

30. diltiazem (class IV) Blocks mainly L-type calcium channels
Decreases SA and Purkinje fiber automaticity, slows conduction through and increases refractory period of AV node
Useful mainly in supraventricular arrhythmias or ventricular arrhythmias caused by coronary spasm
GI disturbances, cardiac toxicity, including heart failure, AV block

31. Long QT syndrome: genetic &/or drug-induced

32. Oral erythromycin and the risk of sudden death from cardiac causes*
Erythromycin is metabolized by CYP3A4
Commonly prescribed drugs increase the AUC of erythromycin by at least 2-fold:
Nitroimidazole antifungals
Diltiazem, Verapamil
Incidence ratio of sudden cardiac death was 5.35 ( , 95% CI) in patients using erythromycin and a CYP3A inhibitor
*Ray et al., NEJM 351: , 2004

33. Drugs and the QT Interval - Caveat Doctor*
Amitriptyline, haloperidol, imipramine, clozapine
2C9
Amitriptyline, tamoxifen
2D6
Amitriptyline, desipramine, imipramine, haloperidol, thioridazine, tamoxifen
3A4
Cisapride, disopyramide, quinidine, pimozide, tamoxifen, erythromycin, clarithromycin
*Liu & Juurlink, NEJM 351: , 2004