Download K channel blockers

Drugs Controlling Myocyte Excitability
and Conduction at the AV node
Singh and Vaughan-Williams Classification
Class III
K channel Blockers
Dofetilide , Dronedarone,
Amiodarone
Class I
Na Channel Blockers
Flecainide
Propafenone
Class II
Beta Blockers
Propranolol
Metoprolol
Class VI
Ca Channel Blockers
Diltiazem
Class V
Other
Digoxin
Two Strategies for Drugs Directly
Treating AFib
• Rhythm Control
– True antiarrhythmic drugs – designed to restore sinus
rhythm by affecting ion channels during the action potential
– Na channel blockers
• Flecainide and propafenone
• Inhibits………
– K channel blockers
• Dofetilide,
• Inhibits…….
– Multi ion channel blockers
• Amiodarone and dronedarone
• All-in-one Na, K, Ca and beta blockers (has rate control
properties)
• Vernakalant, Na and K channel blocker
Antiarrhythmic Drugs
Antiarrhythmic
compound
Cardiac Myocyte
Membrane Effects
route of administration
Presumable
indications
Propafenone/flecainide/vernakalant:
PO/IV
Parox AF
(AFI)
Amiodarone
PO and (?IV)
Persist AF
Dronedarone
(AFI)
multiple effects
PO
Persist AF
Dofetilide
blocks ....
PO
Parox and
Persistent
AFl and AF
PO
AF/Afl: rate
control
Verapamil/Beta blocker
History of Antiarrhythmic Therapy
Beta blockers
Class II
Amiodarone
Class I
1960s
1950s
1990s
1999
1967
Class Ic
Tree extracts
Quinidine From China
1918
1700
1980s
1989
CAST
?
2005
Selective SWORD
Class III
compounds DIAMOND
AFFIRM
• Clinical trials: failure, failure, failure.....
Vaughan-Williams Classification..
CLASS
DRUGS
ACTIVE IN
EFFICACY
TOXICITY
Potential for
PROARRHYTHMIA
IA
Moderately slow conduction
Moderately prolong action potential
Quinidine
Procainamide
Dispyramide
Atria, Ventricles
2+
3+
2+
IB
Minimally slow conduction
Shorten action potential duration
Lidocaine
Mexilitine
Phenytoin
Ventricles
1+
1+
1+
IC
Markedly slow conduction
Minimally prolong action potential duration
Flecainide
Propafenone
Encainide
Atria, Ventricles
3+
1+
3+
II
Beta Blockers
AV node
Ventricles
1+
1+
0
III
Prolong action potential duration
Amiodarone
Bretylium
Sotalol
Ibutilide
Atria, Ventricles
2+
1+
2+
IV
Calcium Channel
blocking drugs
AV node
1+
1+
0
Red = drug effect on action potential. Blue = normal action potential. (Purkinje fiber)
Treatment of ventricular arrhythmias
– Drugs are generally used with a great deal of care due to potential for
pro-arrhythmia (CAST trial in 1980s).
– Ectopic activity arising from DADs/EADs: Not considered serious
unless more than 4-10 beats in a row. Potentially treat with beta
blockers, amiodarone or Na or K channel blockers in a healthy heart.
– Re-entry arrhythmias: e.g. Ventricular tachycardia. Can attempt
suppression in a healthy heart, with Na channel blockers, amiodarone,
dofetilide; otherwise use implantable defribillators (ICD) + Beta
blockade.
– Inherited arrhythmias in children/adults:
The long QT interval syndromes. Tendency for torsades de pointes due
to repolarization instability. Treat with beta blockade to suppress EADs.
If recurrent insert ICD.
Brugada syndrome. Right ventricular disease, due to loss of function of
Scn5A (Na channel). Treat with ICD, or quinidine.
Catecholaminergic Paroxysmal Ventricular Tachycardia (CPVT). Beta
blocker or ICD
Quinidine Exposure can be Pro-Arrhythmic
Implantable cardiac defribrillator
Evolution
Number of Worldwide ICD Implants Per Year
(Ref: Corporate Market Share Database)
ICD Evolution
ICD Components
Action of Class III Drugs is Associated with
QT Prolongation and Torsades
GW
• Unusual spells since age 6
• Almost 20 years later, syncope
during an argument
• Fell off a balcony in 1994
• August 2002: cardiac arrest during
an argument at a sporting event
• Managed with implanted defibrillator
GW
QT=500
RR=940
QTc = 510 ms
Brugada syndrome
What you might want to know
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Flecainide
Propranolol
Amiodarone
Diltiazem
Dofetilide
Digoxin (digitalis)
Atrial fibrillation, Rate and Rhythm control
Treatment of ventricular arrhythmias
including LQTS, Brugada, CPVT
Johnny’s Case
• Previously well 13 year old
• Midst of running, eyes became fuzzy, felt dizzy
and then he fell over
• 1-2 seconds of warning
• Down perhaps 20-30 seconds
• Back to normal within a very brief period
• Doesn’t eat or drink much before being active
Johnny’s Case (cont’d)
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No family history of similar
Paternal grandfather died of MI at 59 yrs
Normal physical exam
Local ECG showed PVCs
Local exercise test showed PVCs and couplets
Benign fainter or not?
BCCH exercise evaluation
Peak exercise
Early recovery
Failed shock
Successful shock
Catecholaminergic Polymorphic VT
• CPVT is a familial arrhythmogenic disorder
characterized by adrenergically mediated
polymorphic ventricular tachyarrhythmias
• Important cause of syncope and SCD in
individuals with a structurally normal heart
• First description CPVT by Reid et al in 1975
CPVT
• Direct relation between adrenergic activation
(physical or emotional stress) and the onset of
arrhythmias
• Exercise test: Typical pattern of bidirectional
VT (reproducible)
• Resting ECG: Normal
• Echo: Normal
• MRI: Normal
• Autopsy: Normal
CPVT
• Average age at first event: 8 ± 2 years
• Syncope triggered by exercise or emotion
• Family history premature sudden deaths in up
to 30 % of patients
CPVT- Natural History
• CPVT highly lethal
disease; if left untreated;
– By age 40: 80% of
CPVT patients will
develop symptoms
(syncope, VT or VF)
– Overall mortality is
30%-50%
Johnny’s Case (cont’d)
• Started on nadolol
• Underwent MRI, blood for genetic testing
• ICD implant