drugs used to treat cardiac arrhythmias. definition: a variation in either the site or rate of...
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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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Passive Ligand-gated
Voltage-gated
R
Na+ K+
Na+ K+
-90 mV
inside
outside
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Na +
Ca 2+
Ca 2+
K +
K +
4
0
12
3
4
K+
Na+
Na/K ATPase
The fast cardiac action potential
-90 mV
+55 mV
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Na + Refractory Period
Effect of local anesthetics on the fast cardiac action potential
Slope phase 0 = conduction velocity Longer RP due to slower recovery from inactivation
Increased threshold
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4
0
12
3
4
K +
K +
Refractory Period
Effect of drugs that block K channels
Increase action potential duration (APD)
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4
0
2
3
4
Ca2+
Ca2+
K+
If
Na, K
Slow cardiac action potential
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4
0
2
3
4
Ca2+
Slope of phase 0 = Conduction velocity
Effect of Ca 2+ channel blockers
Refractory Period
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4
0
2
3
4β agonist
Muscarinic agonists, Adenosine
Drugs affecting automaticity
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Causes of Arrhythmia
1. Automoticity
-ectopic pacemakers
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Ways to decrease automoticity
β(-), Ca++(-),
Na+(-), Ca++(-)
Ach, adenosine
K+(-)
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2 . After depolarizations
Early
Delayed
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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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m m m
h hh
Resting (Closed) Active (Open) Inactive
Sodium Channels
R R
A
I
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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, β blocker or Ca channel blocker
Quinidine is also an alpha receptor antagonist
Effects on ECG QRS, PR, QT
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UsesWide 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 effectsHypotension, reduced cardiac outputProarrhythmia (generation of a new arrhythmia) eg.
Torsades de Points (QT interval) Dizziness, confusion, insomnia, seizure (high dose) Gastrointestinal effects (common) Lupus-like syndrome (esp. procainamide)
Class 1A (cont.)
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Examples of cardiac arrhythmias
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Class 1B agents: Lidocaine, mexiletine, phenytoin
Absorption and eliminationLidocaine: 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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Usesacute : 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
Class 1B (cont.)
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Class 1C agents: Flecainide and propafenone
Absorption and eliminationoral or iv
Effects on cardiac activityvery slow binding offset kinetics (>10 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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UsesWide spectrum
Used for supraventricular arrhythmias (fibrillation and flutter)
Premature ventricular contractions (caused problems)
Wolff-Parkenson-White syndrome
Side effectsProarrhythmia and sudden death especially with chronic use (CAST study) increase ventricular response to supraventricular arrhythmiasCNS and gastrointestinal effects like other local anesthetics
Class 1C (cont.)
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Cardiac Arrhythmia Suppression Trial (CAST)
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Class II agents: propranolol, acebutolol and esmolol
Absorption and eliminationPropranolol: oral, ivEsmolol: 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.)
Usestreating 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 don’t use in partial AV block or ventricular failure
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Class III agents: amiodarone, sotalol, ibutilide, dofetilide
AmiodaroneAbsorption 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 (β block and Ca++ block) speed of AV conduction
Effects on ECG PR, QRS, QT, HR
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Amiodarone (cont.)
UsesVery wide spectrum: effective for most arrhythmias
Side effects: many serious that increase with timePulmonary fibrosisHepatic injuryIncrease LDL cholesterolThyroid diseasePhotosensitivity
May need to reduce the dose of digoxin and class 1 antiarrhythmics
Class III (cont.)
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Sotolol Absorption oral
Cardiac effects APD and refractory period in atrial and ventricular tissue
Slow phase 4 (β blocker)
Slow AV conduction
ECG effects QT, HR
Uses Wide spectrum: supraventricular and ventricular tachycardia Side effects Proarrhythmia, fatigue, insomnia
Class III (cont.)
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IbutilideAbsorption
rapid iv infusion
Cardiac effectspure Ikr channel blocker
also activates inward Na+ current
net result in APD
ECG effects QT
Usesconversion of atrial fibrillation and flutter
Side effects
Torsades de pointes
Class III (cont.)
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DofetilideAbsorption oral
Cardiac effectspure Ikr channel blocker
APD and refractory period
ECG effects QT
Usesmaintain sinus rhythm in pts with atrial fibrillation
Side effects
restricted useTorsades de pointes
Class III (cont.)
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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.)
Usescontrol ventricles during supraventricular tachycardia
convert supraventricular tachycardia (re-entry around AV)
Side effectsCaution when partial AV block is present. Can get asystole if β blocker is on boardCaution when hypotension, decreased CO or sick sinus
Some gastrointestinal problems
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Additional antiarrhythmic agents
AdenosineAdminsitration
rapid i.v. bolus, very short T1/2 (seconds)
Mechanismnatural 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 effectsSlows AV conduction
Usesconvert re-entrant supraventricular arrhythmiashypotension 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 HRUses
treatment of atrial fibrillation and flutter
AtropineMechanism
selective muscarinic antagonist Cardiac effects
block vagal activity to speed AV conduction and increase HRUses
treat vagal bradycardia
Magnesiumtreatment 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