1. Arrhythmias and Antiarrhythmic Drugs
Class I (Na+ channel blockers)
1A: procainamide, quinidine (no longer recommended)
1B: lidocaine
1C: flecainide, propafenone
Class II (-blockers)
non-selective: propranolol
selective: metoprolol
Class III (K+ channel blockers)
amiodarone, sotalol, dofetilide, ibutilide, (azimilide)
Class IV (Ca2+ channel blockers)
verapamil, diltiazem
Others:
adenosine
digoxin
magnesium sulfate
AJ Davidoff ‘09
Treatment Guidelines Medical Letters June 2007

2. What happens to PR interval if AV nodal conduction is prolonged?
What happens to QRS interval if conduction through heart is slowed?
What happens to QT interval if APD is prolonged?

3. Nodal cell firing rate control
ACh  M2 ACh receptors
IK+ , ICa2+, If
NE  1-AR
 If
 ICa2+ (L-type)
Nodal cell firing rate control
ACh = acetylcholine
M-ACh = muscarinic ACh
NE = norepinephrine
-AR =  adrenergic receptor
I = whole cell current
Sherwood Fig 9-24

4. Fast Action Potentials
ITO
Fast Action Potentials
IKr
Outward K+ currents
(delayed rectifiers)
Fast
Na+ current
(INa)
IKs
ITO = transient outward
K+ current

5. Purkinje fiber Optional information
inward positive current
NCX = sodium/calcium exchanger
outward positive current
IKACh = ACh K+ current
ICaL = L type Ca2+ current
INa = Na+ current
Purkinje fiber
transient outward K+ current
ultra rapid K+ current
current activation
rapid K+ current
slow K+ current
‘funny’ current
Nattel and Carlsson 2006 Nature Reviews; Drug Discovery 5:

6. Most arrhythmias result from altered conduction and/or automaticity
Conduction abnormalities
Typically arise from partial depolarization due to injury (e.g., over stretch, ischemia) or abnormal anatomy
Partial or complete block
Accessory conduction pathways
e.g., Wolff-Parkinson-White (WPW) Syndrome
Re-entry
Fibrillation (multi-re-entry loops)

7. Automaticity abnormalities
Originating from nodal cells or ectopic loci
Depolarization-dependent automaticity:
Changes in sinus node firing rate
Prolonged action potential duration (APD)
Early afterdepolarizations
may lead to premature ventricular contractions (PVCs) or multiple extrasystoles
Long QT syndrome
may lead to Torsades de Pointes

8. Supraventricular tachycardias?
In terms of cellular target and action potential (AP) duration, what strategy would you use for:
Rapid nodal firing?
Supraventricular tachycardias?
Premature ventricular contractions (PVCs)?
Ectopic ventricular arrhythmias?
Ventricular tachycardias?
Slow SA or AV nodal depolarizations
Slow atrial cell conduction
Slow AV conduction
Slow ventricular conduction
Prolong ventricular AP duration
Shorten ventricular AP duration
Slow sa or av nodal dep.
2. Slow av conduction
3. Slow ventricular AP duration
4. Slow ventricular conduction/prolong AP duration – depends on where it comes from
5. Prolong ventricular AP duration

9. Strategies to convert fibrillation/tachycardia
For acute atrial fibrillation or supraventricular tach.
Target atrial muscle cells or AV nodal tissue
hyperpolarize membrane
 conduction velocity AV node
Drugs  adenosine
Ca2+ channels
-blockers
digoxin
Want to protect the ventricle
(nodal cell)

10. Target ventricular muscle cells
For V. fib. or V. tach.
Target ventricular muscle cells
conduction velocity
(Vmax)
e.g., block Na+ channels
(Class I drugs)
Vmax is rate of rise. Want to decrease it.
Also want to inc AP duration. Keep membrane depolarized longer so it can’t fire again=slows down.
AP duration (APD)
(refractory period)
e.g., block K+ channels
(now typically preferred over Class I drugs)

11. (preventing re-occurrence)
For Maintenance
(preventing re-occurrence)
Slow AV nodal conduction or frequency of firing
Drugs: digoxin
Ca2+ channel blockers
-blockers
Na+ channel blockers are contraindicated for:
long-term therapy
patients with structural defects (e.g., fibrosis, WPW)
Fibrosis = mi, stent, etc.

12. Cellular models of arrhythmias
Increased automaticity:
 sympathetic activity (e.g., NE or Epi)
 vagal activity (e.g., drug-induced, quinidine)
TP = threshold potential
MDP = maximum diastolic potential
Brenner Box 14-1

13. G&H Fig 10-1

14. Ectopic pacemaker activity
Often due to partial ischemia,
resulting in a more postive resting membrane potential
-90mV
normal
Na+ channels inactivated
-60mV
-40mV
Small cluster of cells that die, the border cells don’t function really well b/c of lack of o2 and nutrients. Cell depolarizes.
Dec Vmax b/c of Na channel inactivation.
Can start taking on characteristics of nodal cells – ectopic pacemaker.
Hyperpolarizing cell can reduce this
Vmax
Conduction

15. Closed
(ready to open)
Resting potential
(-90 mV)
Open
Threshold and activation potentials
(-50 mV to +30mV)
Closed
(unable to open)
Inactivation potentials
(+30 mV to -90mV)
Sherwood Fig 4-7
see also Katzung Fig 14-2

16. Abnormal Impulse Conduction
(hypothetical model)
Katzung Fig 14-8
Normal conduction
Ischemia
Unidirectional block
Re-entry loop

17. Abnormal Impulse Conduction
Ischemic or fibrotic areas slow conduction
Ischemia partially depolarizes resting membrane potential, inactivates some Na+ channels
Slow rate of phase 0 (i.e., rapid depolarization phase) results in slow conduction through heart
Re-entry loops
A model for unidirectional block
Boron Fig

18. Afterdepolarizations
(due to abnormal intracellular Ca2+ regulation)
‘Delayed’
EADs
DADs
EADs  prolonged APD
Clinical arrhythmia:
e.g., torsades de pointes
due to: long QT syndrome
genetic defects (HERG)
disease
drug-induced
DADs  HR or [Ca2+]i
Clinical arrhythmia:
e.g., Ca2+ overload
due to: digoxin or
phosphodiesterase (PDE)
inhibitor toxicity
EAD’s-occur b/c AP is really long. Second upstroke is slower, not using Na channels but using Ca channels. Have very little Na channel component to it.
DAD’s – occur during rapid HR or Ca overload.
Brenner Box 14-1

19. If afterdepolarization is large can trigger PVC
Boron Fig
If afterdepolarization is large can trigger PVC
If sustained, can trigger “run” of extra systoles

20. Nature of Antiarrhythmic Drugs
All have potential of being pro-arrhythmic:
Toxicity may  depress automaticity or
depress conduction velocity
Many are metabolized by cytochrome P450 enzymes
(induced/inhibited, “poor metabolizers”)
Most have a low TI
(especially Na+ channel blockers)
Most show ‘use- (or frequency-) dependent block’
higher affinity for membranes depolarizing frequently
Advantage, because drugs may be selective for abnormally fast rhythms
Generally classified based on primary mechanism of action

21. Class I Na+ channel blockers “use-dependent block” IA Moderate
Na+ channels inactivated
“use-dependent block”
resting/closed
Phase – what it does to Vmax
Repolarization
Class
Phase O
Depression
Action Potential
Duration IA
Moderate
Prolonged
Increased IB
Weak
Shortened
Decreased IC
Strong
No effect
Brody Table 14-3

22. Class 1A Block Na+ channels and K+ channels
No longer drugs of choice
Indications: (alternative DOC)
Atrial fibrillation or flutter
SVT
Ventricular fib or tachycardia
Vmax
APD
Toxicity includes:
Prolongs APD too much
Antimuscarinic effects
(may inhibit vagus n.)
What might happen?
Prolong AP too much get early afterdepolarization. Set up a Torsades
Quinidine (oral)
prototype Class IA
rarely used anymore
Procainamide (oral or IV)
less (-) on vagus
Brenner Fig 4-2

23. Class 1B Block inactivated Na+ channels
Rapidly binds to depolarized membranes
(e.g., during ischemia)
Rapidly dissociates from resting cells
Indications:
Ventricular tachycardia
V. re-entrant loops? (PVCs)
during surgery
No effect on atrial cells
(with short APD)
Vmax
APD
Does nothing to condu velocity, and reduces APD.
Only binds to cells that have a long AP.
Toxicity:
Relatively safe (hemodynamically)
but efficacy is relatively low
Lidocaine (IV only)

24. Class 1C Block open, closed and inactivated Na+ channels
Very slow off rates, not selective for fast rhythms
Indications: (alternative drug of choice)
Sustained ventricular tachycardia
Paroxysmal A. fib or SVT
only with no signs of structural heart disease (e.g., ischemia, hypertrophy)
 Vmax
APD
Toxicity:
Slows conduction (Vmax) too much
Can cause re-entrant loops
(especially v. arrhythmias) 
Block Na channels no matter what state they are in = significant effect on Vmax.
Flecainide
Propafenone (also ~-blocker)
Flecainide   mortality after acute MI
(CAST; cardiac arrhythmia suppression trial)

25. Class II (-blockers) Block -AR on nodal and muscle cells: HR
A-V conduction
(may contractility)
Slow rate of depolarization of phase 4 (pacemaker potential)
Indicated for:
Acute/chronic A. Fib and Flutter
Long term SVT
IV or PO
Brenner Fig 4-4
Propranolol (non-selective)
Metoprolol (1 selective)
Some may be cardioprotective after acute MI

26. Class IV (Ca2+ channel blockers: cardioselective)
Inhibit L-type Ca2+ channels
Effectively raise threshold potential to fire an AP
Use-dependent block, therefore more effective with fast HR
HR, A-V conduction velocity, (may contractility)
Indicated for:
Acute/chronic A. Fib and Flutter
Acute/chronic SVT
Verapamil can also affect contractility. Used mostly in acute settings now.
Diltiazem has less effect on AV nodal cells. For arryth and HTN it is better
Verapamil (more effect on A-V conduction)
Diltiazem (more effect on SA nodal cells)
Dihydropyridines (DHPs) have little antiarrhythmic activity

27. Class III (K+ channel blockers)
Block delayed rectifier channel (IKr)
(as well as other channels)
Indicated for SVT, A. fib, V. fib and V. tach
APD
Amiodarone (DOC)
also Na+, Ca2+ channel blocker
and -blocker
Sotalol
also -blocker (non-selective)
Protect Ventricle from a too high rate or rhythm
Anything that lengthens AP precipitates torsades. Not amio b/c it also blocks na and ca channels as well. Prolonging AP and reducing risk of prolonged AP.
From Opie:
Ibutilide good for terminating AF and A flutter, IV only (extensively metabolized by liver)
Dofetilite (oral only) indicated for cardioconversion of AF and Flutter, and maintenance of normal sinus rhythm with AF and flutter.
Pure Class III blockers
Dofetilide (PO only)
Ibutilide (IV only)
Azimilide (blocks IKr and IKs)
risk of torsades de pointes
(not with amiodarone)

28. Others Antiarrhythmic Drugs
Digoxin
Inhibits Na/K ATPase
Slows A-V conduction (through increasing vagal tone)
Increases refractory period
Indicated for: A. Fib with fast ventricular rate* (and CHF)
Toxicity: complete heart block (narrow TI)
may precipitate Ca2+ overload (e.g., torsades)
Rate Versus Rhythm Control in the Management of Atrial Fibrillation
by D. George Wyse, AHA website, last updated 5/08
Discusses the AFFIRM trial and outcomes suggest that patients with A.fib, should be treated with anticoagulant (warfarin) and control heart rate (rather than rhythm , which is muc harder)
*approaches are now focusing on controling heart rate (with warfarin), rather than rhythm (G. Wyse, AHA website updated 5/08). Thus digoxin is used much less frequently now.

29. Digoxin: Cardiac effects:
Increases intracellular [Na+], increases in Ca2+ (via NCX)
more Ca2+ to trigger SR Ca2+ release,
increases contraction (positive inotropic effects, discussed in heart failure lecture)
Decreases intracellular [K+], depolarizes membrane potential
partially inactivates Na+ channels in fast fibers,
reduces excitability, slows conduction
High affinity to vagus nerve (particularly at the AV node),
increases vagal tone
slows AV nodal conduction
Binds to, and inhibits Na+/K+ ATPase pumps in other tissues (non-cardiac toxicities include visual distrubances -yellow hues), with highest affinity to cardiac and vagal nerve.
Toxicitity incr with low k

30. Opens K+ channels  hyperpolarizes membrane
Adenosine
Opens K+ channels  hyperpolarizes membrane
(also blocks Ca2+ channels)
Selective for coronary arteries and atrial muscle cells
(not ventricular myocytes)
Slows SA nodal firing
Slows A-V conduction
Very short T1/2 (seconds)
Indicated for ‘cardioconversion’
Slows HR by hyperpolarizing membrane.
Magnesium
Inhibits Ca2+ influx through L-type Ca2+ channels
Indicated for:
Drug-induced torsades
Digoxin-induced ventricular arrhythmias

31. Triggered activity due too much intracellular Ca2+
[Ca2+]i  Na/Ca exchange  [Na+]i
(3Na+(in): 1Ca2+(out)) (depolarize membrane)
Makes NA/Ca exchanger reverse and bring in Na and Ca out. More Na cuases depolarization, etc.
Mg blocks Lca to diminsh arrhythmias.
Mg2+
(for torsades)
Open L-type Ca2+ channels

32. Reduces action potential duration (APD) Slows conduction
Effects of serum potassium appear paradoxical: contrary to what would be predicted by changes in electrochemical gradient
Hyperkalemia
Reduces action potential duration (APD)
Slows conduction
Decreases pacemaker rate and arrhythmogenesis
(leading to bradiacardia and perhaps asytole)
Hypokalemia (more detrimental than hyperkalemia)
Prolongs APD
Increases pacemaker rate and arrhythmogenesis
(increasing risk of ventricular fibrillations)
Increases sensitivity to K+ channel blockers
resulting in accentuated APD prolongation with risk of Torsades de Pointes
Katzung 2009 p. 228
Ranolazine
Recently approved for chronic stable angina
Prolongs QT interval
(maybe by inhibiting late Na+ current or delayed K+ rectifier current)

33. Supraventricular tachycardias?
In terms of cellular target and action potential duration, what strategy would you use for:
Rapid nodal firing?
Supraventricular tachycardias?
Premature ventricular contractions (PVCs)?
Ventricular tachycardias?
Na+ channel blockers
-blockers
K+ channel blockers
Ca2+ channel blockers
Ca Channel blocker
2. BB or CaB
3. CaB, BB
4. KB

34. Atrial fibrillation or flutter:
Acute
Rate control: (IV) verapamil, diltiazem, -blockers, digoxin
Chronic
Rate control: verapamil, diltiazem, -blockers, digoxin
Maintenance of sinus rhythm:
amiodarone, sotalol, flecainide, propafenone, dofetilide
Other SVTs:
Acute
(vagotonic maneuvers, e.g., carotid sinus massage)
(IV) adenosine, verapamil, diltiazem
Chronic
-blockers, verapamil, diltiazem, flecainide, propafenone, amirodarone, sotalol, digoxin
According to Treatment Guidelines, Medical Letters 2007

35. PVCs or non-sustained V. tach:
Asymptomatic
no therapy
Symptomatic (flecainide is contraindicated post-MI)
-blockers (post MI improves mortality rates)
Sustained V. tach. or V. fib:
Acute
DC cardioversion is safest
amiodarone
Chronic
Implantable cardiac defribillator (ICD) (NEJM Jan 20, 2005)
amiodarone, plus a -blocker
NEJM
ICD improved survival in CHF patients with stage II and III, with LVEF equal or less than 35%, by 23% over 45 months
amiodarone did not improve survival
According to Medical Letters

36. Alternative Classification based on target
Drug therapy for supraventricular arrhythmias
Adenosine (IV only)
Verapamil
Diltiazem
Esmolol (IV only)
Ibutilide (IV only)
Dofetilide (oral only)
Drug therapy for ventricular arrhythmias
Procainamide (not preferred)
Lidocaine (IV only)
Flecainide or Propafenone (oral, not approved for IV in US)
Sotalol
Amiodarone
LH Opie 2004