Drugs used to treat cardiac arrhythmias

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Drugs used to treat cardiac arrhythmias
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Definition a variation in either the site or
rate of cardiac impulse formation, and/or a
variation in the sequence of cardiac impulse
propagation.
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Na
K
outside
R
-90 mV
Ligand-gated
Voltage-gated
Passive
inside
K
Na
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The fast cardiac action potential
Ca 2
Ca 2
1
55 mV
K
2
K
3
Na
Na
0
4
4
K
-90 mV
Na/K ATPase
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Effect of local anesthetics on the fast cardiac
action potential
Refractory Period
Na
Longer RP due to slower recovery from inactivation
Slope phase 0 conduction velocity
Increased threshold
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Effect of drugs that block K channels
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Refractory Period
2
K
3
K
0
4
4
Increase action potential duration (APD)
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Slow cardiac action potential
Ca2
2
Ca2
K
3
0
If
4
4
Na, K
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Effect of Ca 2 channel blockers
Refractory Period
2
Ca2
3
0
4
4
Slope of phase 0 Conduction velocity
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Drugs affecting automaticity
2
3
0
4
4
ß agonist
Muscarinic agonists, Adenosine
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Causes of Arrhythmia

• Automoticity
• -ectopic pacemakers

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Ways to decrease automoticity
ß(-), Ca(-),
Na(-), Ca(-)
Ach, adenosine
K(-)
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2 . After depolarizations
Delayed
Early
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3. re-entry
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Class Action Drugs
I A. Moderate phase 0 Quinidine,
procainamide I B. No change in phase
0 Lidocaine I C. Marked phase
0 Flecainide II Beta-adrenergic
blockers Propranolol, esmolol
III Prolong repolarization Amiodarone,
Sotolol Dofetalide, ibutilide
IV Calcium channel blockers Verapamil,
diltiazem
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Class 1 Local anesthetics
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Sodium Channels
Resting (Closed)
Active (Open)
Inactive
m
m
m
h
h
h
I
A
R
R
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Local anesthetics bind to and release from the
Na channel at different rates
Phasic/frequency dependent
tonic
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Class 1A agents Procainamide, quinidine,
disopyramide    Absorption and elimination
(oral or iv) Effects on cardiac activity
Intermediate binding offset kinetics ?
conduction (? phase 0 of the action potential
(Na)) ? refractory period (? APD (K) and ?
Na inactivation) ? automoticity (? slope
of phase 4, fast potentials) ? increase
threshold (Na) Quinidine has anticholinergic
(atropine like action) to speed AV conduction
used with digitalis, ß blocker or Ca channel
blocker Quinidine is also an alpha receptor
antagonist Effects on ECG         ? QRS, ?
PR, ?QT
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Class 1A (cont.)
Uses Wide spectrum Quinidine maintain sinus
rhythms in atrial fibrillation and flutter and
to prevent recurrent tachycardia and fibrillation
     Procainamide acute treatment of
supraventricular and ventricular arrhythmias
  Side effects Hypotension, reduced cardiac
output Proarrhythmia (generation of a new
arrhythmia) eg. Torsades de Points (?QT
interval)               Dizziness, confusion,
insomnia, seizure (high dose)              
Gastrointestinal effects (common)               Lu
pus-like syndrome (esp. procainamide)
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Examples of cardiac arrhythmias
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Class 1B agents Lidocaine, mexiletine,
phenytoin Absorption and elimination Lidocaine
iv only             Tocainide and mexiletine
oral        Effects on cardiac activity Fast
binding offset kinetics No change in phase 0 in
normal tissue (no tonic block)  APD slightly
decreased (normal tissue) ? increase threshold
(Na)              ? phase 0 conduction in
fast beating or ischemic tissue,    Effects on
ECG None in normal, in fast beating or ischemic
? QRS
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Class 1B (cont.)
Uses acute Ventricular tachycardia and
fibrillation (esp. during ischemia) Not used
in atrial arrhythmias or AV junctional
arrhythmias       Side effects                
Less proarrhythmic than Class 1A (less QT
effect)               CNS effects dizziness,
drowsiness
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Class 1C agents Flecainide and
propafenone Absorption and elimination oral or
iv                  Effects on cardiac
activity very slow binding offset kinetics (gt10
s)  Substantially ? ? phase 0 (Na) in
normal ? automoticity (? threshold) ? APD
(K) and ? refractory period, esp in
rapidly depolarizing atrial tissue.             
        Effects on ECG                    ? PR,
?QRS, ?QT
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Class 1C (cont.)
Uses Wide spectrum Used for supraventricular
arrhythmias (fibrillation and
flutter)               Premature ventricular
contractions (caused problems)
Wolff-Parkenson-White syndrome Side
effects Proarrhythmia and sudden death
especially with chronic use (CAST study)
increase ventricular response to
supraventricular arrhythmias CNS and
gastrointestinal effects like other local
anesthetics
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Cardiac Arrhythmia Suppression Trial (CAST)
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Class II agents propranolol, acebutolol and
esmolol Absorption and elimination Propranolol
oral, iv Esmolol iv only (very short acting
T½, 9 min) Cardiac effects ? APD and
refractory period in AV node to slow AV
conduction velocity ? decrease phase 4
depolarization (catecholamine
dependent) Effects on ECG                ? PR,
? HR
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Class II (cont.) Uses treating sinus and
catecholamine dependent tachy
arrhythmias converting reentrant arrhythmias in
AV protecting the ventricles from high atrial
rates (slow AV conduction) Side effects
       bronchospasm              hypotension     
          dont use in partial AV block or
ventricular failure
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Class III agents amiodarone, sotalol,
ibutilide, dofetilide Amiodarone Absorption and
elimination oral or iv (T 1/2 about 3
months) Cardiac effects ? increase refractory
period and ? APD (K)              ? phase 0
and conduction (Na) ? threshold
             ? phase 4 (ß block and Ca block)
             ? speed of AV conduction Effects on
ECG ? PR,? QRS, ? QT, ? HR
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Class III (cont.)
Amiodarone (cont.) Uses Very wide spectrum
effective for most arrhythmias Side effects
many serious that increase with time Pulmonary
fibrosis Hepatic injury Increase LDL
cholesterol Thyroid disease Photosensitivity Ma
y need to reduce the dose of digoxin and class 1
antiarrhythmics
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Class III (cont.)
Sotolol Absorption oral Cardiac effects ? APD
and refractory period in atrial and ventricular
tissue Slow phase 4 (ß blocker) Slow AV
conduction ECG effects ? QT, ? HR Uses   Wide
spectrum supraventricular and ventricular
tachycardia                     Side
effects    Proarrhythmia, fatigue, insomnia
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Class III (cont.)
Ibutilide Absorption rapid iv infusion Cardiac
effects pure Ikr channel blocker also
activates inward Na current net result in ?
APD ECG effects ?QT Uses conversion of
atrial fibrillation and flutter             Side
effects Torsades de pointes
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Class III (cont.)
Dofetilide Absorption oral Cardiac
effects pure Ikr channel blocker ? APD and
refractory period ECG effects ?
QT Uses maintain sinus rhythm in pts with
atrial fibrillation                  Side
effects restricted use Torsades de pointes
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Class IV agents verapamil and
diltiazem Administration verapamil oral or
i.v. diltiazem oral Cardiac effects slow
conduction through AV (Ca) ? refractory
period in AV node ? slope of phase 4 in SA to
slow HR Effects on ECG ? PR, ?? HR (depending
of blood pressure response and baroreflex)
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Class IV (cont.) Uses control ventricles during
supraventricular tachycardia convert
supraventricular tachycardia (re-entry around
AV) Side effects Caution when partial AV block
is present. Can get asystole if ß blocker
is on board Caution when hypotension, decreased
CO or sick sinus Some gastrointestinal problems
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Additional antiarrhythmic agents Adenosine Admins
itration                     rapid i.v. bolus,
very short T1/2 (seconds) Mechanism natural
nucleoside that binds A1 receptors and activates
K currents in AV and SA node ? APD,
hyperplarization ? ?HR ? Ca currents - ?
refractory period in AV node Cardiac
effects Slows AV conduction Uses convert
re-entrant supraventricular arrhythmias hypotensi
on during surgery, diagnosis of CAD
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Digioxin (cardiac glycosides) Mechanism enhances
vagal activity (? K currents, ? Ca currents, ?
refractory period slows AV conduction and
slows HR Uses treatment of atrial fibrillation
and flutter Atropine Mechanism selective
muscarinic antagonist Cardiac effects block
vagal activity to speed AV conduction and
increase HR Uses treat vagal bradycardia Magnesi
um treatment for tachycardia resulting from long
QT
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DC Cardioversion (electric shock)
Treatment of choice for unstable,
life-threatening cardiac arrhyghmias.
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Ablation therapy
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Mechanical devices Implantable defibrillator
for sudden death has been shown to be more
effective than pharmacological therapy for
increasing longevity