1. Drugs used to treat cardiac arrhythmias

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

3. Na+ K+ K+ Na+ outside R Passive Ligand-gated Voltage-gated inside
-90 mV
Passive
Ligand-gated
Voltage-gated
inside K+
Na+

4. The fast cardiac action potential1
+55 mV 2
K + 3
K +
Na +
Na+ 4 4 K+
-90 mV
Na/K ATPase

5. 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

6. Effect of drugs that block K channels1
Refractory Period 2
K + 3
K + 4 4
Increase action potential duration (APD)

7. Slow cardiac action potential2
Ca2+ K+ 3 If 4 4
Na, K

8. Effect of Ca 2+ channel blockers
Refractory Period 2
Ca2+ 3 4 4
Slope of phase 0 = Conduction velocity

9. Drugs affecting automaticity2 3 4 4
β agonist
Muscarinic agonists, Adenosine

11. Automoticity -ectopic pacemakers
Causes of Arrhythmia
Automoticity
-ectopic pacemakers

12. Ways to decrease automoticity
β(-), Ca++(-),
Na+(-), Ca++(-)
Ach, adenosine
K+(-)

13. 2 . After depolarizations
Delayed
Early

14. 3. re-entry

16. 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

17. Class 1: Local anesthetics

18. 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

19. Local anesthetics bind to and release from the Na+ channel at different rates
Phasic/frequency dependent
tonic

20. 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

21. 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)

22. Examples of cardiac arrhythmias

23. 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

24. 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

25. 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

26. 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

27. Cardiac Arrhythmia Suppression Trial (CAST)

28. 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

29. 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

30. 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

31. 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

32. 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

33. 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

34. 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

35. 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)

36. 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

37. 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

38. 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

39. DC Cardioversion (electric shock)
Treatment of choice for unstable, life-threatening cardiac arrhyghmias.

40. Ablation therapy

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