Class I (Na + channel blockers) 1A: procainamide, quinidine (no longer recommended)
description
Transcript of Class I (Na + channel blockers) 1A: procainamide, quinidine (no longer recommended)
Class I (Na+ channel blockers)1A: procainamide, quinidine (no longer recommended)1B: lidocaine1C: flecainide, propafenone
Class II (-blockers)non-selective: propranololselective: metoprolol
Class III (K+ channel blockers)amiodarone, sotalol, dofetilide, ibutilide, (azimilide)
Class IV (Ca2+ channel blockers)verapamil, diltiazem
Others:adenosinedigoxinmagnesium sulfate
Arrhythmias and Antiarrhythmic Drugs
AJ Davidoff ‘09Treatment Guidelines Medical Letters June 2007
What happens to QRS interval if conduction through heart is slowed?
What happens to QT interval if APD is prolonged?
What happens to PR interval if AV nodal conduction is prolonged?
ACh M2 ACh receptors
IK+ , ICa2+, If
NE 1-AR
If
ICa2+ (L-type)
Sherwood Fig 9-24
ACh = acetylcholineM-ACh = muscarinic AChNE = norepinephrine-AR = adrenergic receptorI = whole cell current
Nodal cell firing rate control
Fast Action Potentials
FastNa+ current(INa)
IKr
IKs
Outward K+ currents(delayed rectifiers)
ITO = transient outward K+ current
ITO
Nattel and Carlsson 2006 Nature Reviews; Drug Discovery 5:1034-1049
ultra rapid K+ current
rapid K+ currentslow K+ current
transient outward K+ current
‘funny’ current
inward positive current
outward positive currentNCX = sodium/calcium exchangerIKACh = ACh K+ currentICaL = L type Ca2+ currentINa = Na+ current
current activation
Optional information
Pur
kin j
e fib
er
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 blockAccessory conduction pathways
e.g., Wolff-Parkinson-White (WPW) SyndromeRe-entryFibrillation (multi-re-entry loops)
Automaticity abnormalitiesOriginating 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
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
Strategies to convert fibrillation/tachycardiaFor acute atrial fibrillation or supraventricular tach.
Target atrial muscle cells or AV nodal tissuehyperpolarize membrane conduction velocity AV node
Drugs adenosineCa2+ channels-blockersdigoxin
(nodal cell)
For V. fib. or V. tach.Target ventricular muscle cells
AP duration (APD) (refractory period) e.g., block K+ channels
(now typically preferred over Class I drugs)
conduction velocity (Vmax) e.g., block Na+ channels
(Class I drugs)
For Maintenance(preventing re-occurrence)
Slow AV nodal conduction or frequency of firingDrugs: digoxin
Ca2+ channel blockers-blockers
Na+ channel blockers are contraindicated for:•long-term therapy•patients with structural defects (e.g., fibrosis, WPW)
Cellular models of arrhythmias
Increased automaticity: sympathetic activity (e.g., NE or Epi) vagal activity (e.g., drug-induced, quinidine)
Brenner Box 14-1TP = threshold potentialMDP = maximum diastolic potential
G&H Fig 10-1
Na+ channels inactivated
-60mV -40mV
Ectopic pacemaker activity
-90mV
normal
Often due to partial ischemia, resulting in a more postive resting membrane potential
VmaxConduction
Sherwood Fig 4-7 see also Katzung Fig 14-2
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)
Normal conduction
Re-entry loopUnidirectional block
Ischemia
Katzung Fig 14-8Abnormal Impulse Conduction(hypothetical model)
A model for unidirectional block
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
Boron Fig. 20-14
Afterdepolarizations(due to abnormal intracellular Ca2+ regulation)
EADs prolonged APD
Clinical arrhythmia: e.g., torsades de pointesdue to: long QT syndrome
genetic defects (HERG)diseasedrug-induced
EADsDADs
‘Delayed’
DADs HR or [Ca2+]i
Clinical arrhythmia: e.g., Ca2+ overloaddue to: digoxin or phosphodiesterase (PDE) inhibitor toxicity
Brenner Box 14-1
Boron Fig. 20-15
If afterdepolarization is large can trigger PVCIf sustained, can trigger “run” of extra systoles
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
RepolarizationClass Phase O Depression
Action Potential Duration
IA Moderate Prolonged IncreasedIB Weak Shortened DecreasedIC Strong No effect No effect
Brody Table 14-3
Class INa+ channel blockers
“use-dependent block”
Na+ channels inactivated
resting/closed
Vmax APD
Quinidine (oral)prototype Class IArarely used anymore
Procainamide (oral or IV)less (-) on vagus
Class 1A Block Na+ channels and K+ channelsNo longer drugs of choiceIndications: (alternative DOC)•Atrial fibrillation or flutter•SVT•Ventricular fib or tachycardia
Toxicity includes:•Prolongs APD too much•Antimuscarinic effects(may inhibit vagus n.)
What might happen?
Brenner Fig 4-2
Class 1B Block inactivated Na+ channels
Indications:•Ventricular tachycardia •V. re-entrant loops? (PVCs)•during surgeryNo effect on atrial cells (with short APD)
Toxicity:•Relatively safe (hemodynamically)but efficacy is relatively low
Rapidly binds to depolarized membranes(e.g., during ischemia)
Rapidly dissociates from resting cells
Vmax
APD
Lidocaine (IV only)
Flecainide mortality after acute MI(CAST; cardiac arrhythmia suppression trial)
Vmax
APD
Class 1C Block open, closed and inactivated Na+ channels
Indications: (alternative drug of choice)Sustained ventricular tachycardiaParoxysmal A. fib or SVTonly with no signs of structural heart disease (e.g., ischemia, hypertrophy)
Very slow off rates, not selective for fast rhythms
Toxicity:•Slows conduction (Vmax) too much•Can cause re-entrant loops(especially v. arrhythmias)
FlecainidePropafenone (also ~-blocker)
Class II (-blockers)
Some may be cardioprotective after acute MI
Propranolol (non-selective)Metoprolol (1 selective)
Brenner Fig 4-4
Block -AR on nodal and muscle cells:
HRA-V conduction(may contractility)
Slow rate of depolarization of phase 4 (pacemaker potential)
Indicated for:Acute/chronic A. Fib and FlutterLong term SVT
IV or PO
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 HRHR, A-V conduction velocity, (may contractility)
Indicated for:Acute/chronic A. Fib and FlutterAcute/chronic SVT
Verapamil (more effect on A-V conduction)
Dihydropyridines (DHPs) have little antiarrhythmic activity
Diltiazem (more effect on SA nodal cells)
Block delayed rectifier channel (IKr)(as well as other channels)
APD
Class III (K+ channel blockers)
Amiodarone (DOC)also Na+, Ca2+ channel blockerand -blockerSotalolalso -blocker (non-selective)
Indicated for SVT, A. fib, V. fib and V. tach
Pure Class III blockersDofetilide (PO only)Ibutilide (IV only)Azimilide (blocks IKr and IKs)
risk of torsades de pointes (not with amiodarone)
Others Antiarrhythmic DrugsDigoxinInhibits 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)
*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.
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 potentialpartially inactivates Na+ channels in fast fibers,
reduces excitability, slows conduction
High affinity to vagus nerve (particularly at the AV node), increases vagal toneslows 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.
AdenosineOpens K+ channels hyperpolarizes membrane
(also blocks Ca2+ channels)Selective for coronary arteries and atrial muscle cells
(not ventricular myocytes)Slows SA nodal firingSlows A-V conduction
Very short T1/2 (seconds)Indicated for ‘cardioconversion’
MagnesiumInhibits Ca2+ influx through L-type Ca2+ channelsIndicated for:
Drug-induced torsadesDigoxin-induced ventricular arrhythmias
Triggered activity due too much intracellular Ca2+
[Ca2+]i Na/Ca exchange [Na+]i
(3Na+(in): 1Ca2+(out)) (depolarize membrane)
Open L-type Ca2+ channelsMg2+
(for torsades)
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
RanolazineRecently approved for chronic stable anginaProlongs QT interval (maybe by inhibiting late Na+ current or delayed K+ rectifier
current)
Katzung 2009 p. 228
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
Atrial fibrillation or flutter:Acute •Rate control: (IV) verapamil, diltiazem, -blockers, digoxinChronic•Rate control: verapamil, diltiazem, -blockers, digoxin•Maintenance of sinus rhythm: amiodarone, sotalol, flecainide, propafenone, dofetilide
According to Treatment Guidelines, Medical Letters 2007
Other SVTs:Acute• (vagotonic maneuvers, e.g., carotid sinus massage)• (IV) adenosine, verapamil, diltiazemChronic-blockers, verapamil, diltiazem, flecainide, propafenone, amirodarone, sotalol, digoxin
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:AcuteDC cardioversion is safest• amiodarone
Chronic• Implantable cardiac defribillator (ICD) (NEJM Jan 20, 2005)• amiodarone, plus a -blocker
According to Medical Letters
Alternative Classification based on targetDrug therapy for supraventricular arrhythmias
Adenosine (IV only)VerapamilDiltiazemEsmolol (IV only)Ibutilide (IV only)Dofetilide (oral only)
Drug therapy for ventricular arrhythmiasProcainamide (not preferred)Lidocaine (IV only)Flecainide or Propafenone (oral, not approved for IV in US)SotalolAmiodarone
LH Opie 2004