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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+ K+ Na+ outside R Passive Ligand-gated Voltage-gated inside
-90 mV Passive Ligand-gated Voltage-gated inside K+ Na+
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The fast cardiac action potential
1 +55 mV 2 K + 3 K + Na + Na+ 4 4 K+ -90 mV Na/K ATPase
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Na + 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
1 Refractory Period 2 K + 3 K + 4 4 Increase action potential duration (APD)
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Slow cardiac action potential
2 Ca2+ K+ 3 If 4 4 Na, K
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Effect of Ca 2+ channel blockers
Refractory Period 2 Ca2+ 3 4 4 Slope of phase 0 = Conduction velocity
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Drugs affecting automaticity
2 3 4 4 β agonist Muscarinic agonists, Adenosine
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Automoticity -ectopic pacemakers
Causes of Arrhythmia 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
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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m m m h h h Sodium Channels I A R R 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, β 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) Lupus-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 (>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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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 don’t use in partial AV block or ventricular failure
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Class III agents: amiodarone, sotalol, ibutilide, dofetilide
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 (β block and Ca++ block) speed of AV conduction Effects on ECG PR, QRS, QT, HR
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Amiodarone (cont.) Class III (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 May 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 (β 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 β blocker is on board Caution when hypotension, decreased CO or sick sinus Some gastrointestinal problems
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Additional antiarrhythmic agents Adenosine
Adminsitration 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 hypotension 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 selective muscarinic antagonist Cardiac effects block vagal activity to speed AV conduction and increase HR treat vagal bradycardia Magnesium 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
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