Drugs used to treat cardiac arrhythmias

Definition: a variation in either the site or rate of cardiac impulse formation, and/or a variation in the sequence of cardiac impulse propagation.

Passive Ligand-gated

Voltage-gated

R

Na+ K+

Na+ K+

-90 mV

inside

outside

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

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

4

0

12

3

4

K +

K +

Refractory Period

Effect of drugs that block K channels

Increase action potential duration (APD)

4

0

2

3

4

Ca2+

Ca2+

K+

If

Na, K

Slow cardiac action potential

4

0

2

3

4

Ca2+

Slope of phase 0 = Conduction velocity

Effect of Ca 2+ channel blockers

Refractory Period

4

0

2

3

4β agonist

Muscarinic agonists, Adenosine

Drugs affecting automaticity

Causes of Arrhythmia

1. Automoticity

-ectopic pacemakers

Ways to decrease automoticity

β(-), Ca++(-),

Na+(-), Ca++(-)

Ach, adenosine

K+(-)

2 . After depolarizations

Early

Delayed

3. re-entry

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

Class 1: Local anesthetics

m m m

h hh

Resting (Closed) Active (Open) Inactive

Sodium Channels

R R

A

I

Local anesthetics bind to and release from the Na+ channel at different rates

Phasic/frequency dependent

tonic

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

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.)

Examples of cardiac arrhythmias

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

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.)

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

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.)

Cardiac Arrhythmia Suppression Trial (CAST)

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

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

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

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.)

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.)

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.)

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.)

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)

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

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

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

DC Cardioversion (electric shock)

Treatment of choice for unstable, life-threatening cardiac arrhyghmias.

Ablation therapy

Mechanical devices

Implantable defibrillator: for sudden death has been shown to be more effective than pharmacological therapy for increasing longevity