1. Antiarrhythmic Agents

2. Learning Objectives Explain the mechanism of antiarrhythmic agents
List classifications of antiarrhythmic agents
Summarize the pharmacological effects, clinical applications and ADR of Quinidine, Lidocaine, Phenytoin, Propranolol , Amiodarone and Verapamil

3. arrhythmia
Cardiac arrhythmia is a frequent problem in clinical practice.
Disturbances of Impulse formation or conduction

4. Cardiac electrophysiology
Inside cell: K+ ; Outside cell: Na+, Ca++
Ion channel status/
Transmembrane movement
Membrane
potential

5. Normal action potential in ventricular myocytes and Purkinje cells,
Reproduced from Katzung & Trevor’s Pharmacology Examination & Board Review, 9th edition, McGraw-Hill, 2010.

6. Action potential (AP) and Phase 0-4
phase 0---reactivity---conduction--- Na +
phase K +
phase 2, 3---afterdepolarization--- Ca ++
phase 4---automaticity--- Na +
Action potential duration /Effective Refractory Period: membrane potential~-60 mV

7. Effects of Group I drugs on the action potential and ion currents in a typical ventricular cell or Purkinje cell.
Reproduced from Katzung & Trevor’s Pharmacology Examination & Board Review, 9th edition, McGraw-Hill, 2010.

8. Mechanisms of arrhythmia
1. disturbances of impulse formation
Automaticity
Maximum Diastolic Potential , slope of phase 4 depolarization , threshold potential
Afterdepolarization
Early (P2,3: Ca inflow )
Delayed (P4:Ca Na inflow )

9. Mechanisms of arrhythmia
2. Abnormality of impulse conduction
Reentry (circus movement)

10. cardiac conduction system

11. Normally, electrical excitation is transmitted around the circuit, and becomes extinguished at the other end of the circuit due to collision of impulses.
Normal conduction

12. Forward impulse obstructed and extinguished
Depressed region
Unidirectional block

13. Retrograde impulse travels around the obstacle because the conduction time is longer than the refractory period
Retrograde impulse

14. Retrograde impulse reexcites the tissue, and the reentry arrhythmia is extablished

15. For reentry to occur, three conditions must coexist
There must be the presence of an anatomically or functionally defined circuit
There must be unidirectional block at some point in the circuit; that is, conduction must die out in one direction but continue in the opposite direction
Conduction time around the circuit must be long enough that the retrograde impulse does not enter refractory tissue as it travels around the obstacle; that is, the conduction time must exceed the effective refractory period.

16. 16-word pithy formula – “CURE”
单向阻滞
有路可通
Circuit c
Unidirectional block U 折返
16 字诀
超不应期 E R
逆向传导
Exceed ERP
Retrograde conduction

17. Electrophysiologic effects of Antiarrhythmic drugs
1.To decrease Automaticity
Increase MDP,
Slow down slope of phase 4 ,
increase threshold potential (TP)

18. Electrophysiologic effects of Antiarrhythmic drugs
2.To reduce post depolarization and triggered activity
antagonize cellular Ca to impaired EAD
Inhibit Na influx to impaired LAD

19. Electrophysiologic effects of Antiarrhythmic drugs
3.To change membrane responsiveness, so to change the conduction, hence to terminate reentry
To increase MR so suppress unidirectional block
To decrease MR so change unidirectional block to bidirectional block

20. Electrophysiologic effects of Antiarrhythmic drugs
4.To change ERP and APD so terminate reentry
Absolutely prolong ERP and APD
Relatively prolong ERP(shorten APD)
Symmetric ERP

21. 20-word pithy formula – “AdCREA”
去后除极
降自律性 A Ad
After-
depolarization
Automaticity
Antiarrhythmia E C
减慢传导
延不应期
Conduction R
ERP
消除折返
Reentry

22. Antiarrhythmic agents
Ⅰ：sodium channel antagonists
ⅠA ：block Na+ Channel ++, quinidine
ⅠB ： ，lidocaine
ⅠC ： ，flecainide
Drugs with class 1A action prolong the APD and dissociate from the channel with intermediate kinetics; drugs with class 1B action shorten the APD and dissociate from the channel with rapid kinetics; and drugs with class 1C action have minimal effects on the APD and dissociate from the channel with slow kinetics.

23. Antiarrhythmic agents
Ⅱ： β -R blockers: propranolol
Class 2 action is sympatholytic Drugs with this action reduce -adrenergic activity in the heart.
Ⅲ： selective prolong APD: amiodarone
Class 3 action manifests as prolongation of repolarization. Most drugs block the rapid component of the delayed rectifier potassium channel, IKr.
Ⅳ： CCBs: verapamil

24. Antiarrhythmic agents-IA
IA Quinidine
Mechanism ( )Na---phase-0,4
Pharmacologic effects
conduction
automaticity(pukinje fiber )
ERP, APD
Block alpha adrenoceptor so cause vasodilation
Anti-M-cholinoceptor to increase heart rate

25. Antiarrhythmic agents-IA
Clinical use (broad –spectrum )
Common in Atrial Fibrillation and flutter, occationally in ventricular tachycardia.
ADR:
1. Cinchonism (headache, dizziness, tinnitus)
2. Gastrointestinal effects (diarrhea,nausea,vomiting)
3. allergic reaction(angioneurotic edema)
4. Quinidine syncope (excessive QT interval prolongation and torsade de pointes arrhythmia)

26. Antiarrhythmic agents-IA
IA procainamide
Mechanism : similar to quinidine
Pharmacologic effects
automaticity(pukinje fiber )
conduction
ERP,APD
Adverse reaction:
cardiotoxic effects;
Extracardiotoxicity: lupus-like syndrome

27. Drugs cause the lupus-like syndrome
笨扑一惊，狼来了！
苯妥英钠 Phenytoin
普鲁卡因胺 Procainamide
异烟肼 Isoniazide
肼屈嗪 Hydralazine

28. Antiarrhythmic agents-Ib
IB- lidocaine
Mechanism: Na, + K
Pharmacologic effects
+ K potential recover to the resting potential
automaticity ( slow velocity of P-4 in PF )
terminate reentry

29. Clinic use : Adverse reaction :
first choice for ventricular tachycardia and fibrillation after myocardial infarction
Adverse reaction :
Least cardiotoxic effects
Neurologic: paresthesias,tremor, convulsions, slurred speech, hearing disturbances, lightheadedness

30. Antiarrhythmic agents-Ib
IB-phenytoin sodium
Mechanism similar to lidocaine
Pharmacologic effects
* decrease automaticity in PF
* compete with cardiac glycoside for combination of Na-K-ATPase
Clinic use:
to treat digoxin-induced arrhythmias

31. Antiarrhythmic agents-Ic
IC-Propafenone
Mechanism
Na, (0,4), β-R
Pharmacologic effects
automaticity
conduction
Clinic use: supraventricular arrhythmias
ADR: QT ;metallic taste,constipation

32. Antiarrhythmic agents-II
β-R antagonists: propranolol
Mechanism
β-R, Na, ERP
Clinic use
SVT, Af, hyperthyrosis
ADR
SB, AVB, HF, Hypotension, Asthma.

33. Antiarrhythmic agents-III Selectively prolong repolarization
Mechanism (Amiodarone) : block K+ ,Na+, Ca++
Pharmacological actions
• Reduce automaticity in sinoatrial node and PF
• slow conduction in atrioventricular node and PF
• prolong ERP in atria and PF

34. Antiarrhythmic agents-III Selectively prolong repolarization
Clinic uses :
• Supraventricular(atrial fibrillation), ventricular (tachycardia/fibrillation) tachyarrhythmias
ADRs: photosensitive skin, thyroid abnormalities(hypo- and hyper-), pulmonary fibrosis, corneal microdeposits, neurological and gastrointestinal disturbances

35. Antiarrhythmic agents-IV
CCB: verapamil
Pharmacological actions
• reduce automaticity in sinoatrial node and atrial-ventricular node by slowing P-4 velocity
• slow conduction in atrioventricular node
• prolong ERP
Suppress afterdepolarization
Clinic uses:
• to prevent or terminate recurrence of paroxysmal SVT;
• to reduce the ventricular rate in patients with atrial fibrillation

36. Antiarrhythmic agents
Drugs to treate Bradycardia
Atropine, Isoprenaline

37. Antiarrhythmic agents-ADR
Common ADR of Antiarrhythmic agents
is proarrhythmia.

38. Summary IA IB IC II III IV Agent Na - - K- Na- K+ Na- - - Na-K+ - β R
Quni.
Lido.
Propa.
Propra.
Sotalol
Ami.
Ver.
Ion Ch.
Na - - K-
Na- K+
Na- - -
Na-K+
- β R
Na-K--
Ca-
Ca-- AP
0,4
0,2,4
0,1-3
0,2
ERP +
- (r+)
-(r+) ++
ClinicU
AF, Af
PVC,Vf
PVC,VT
SVT,pvc
SVT,V
SVT
ADR
Cinchoni -sm,gastrointestine
QT+
CNS, - breath
BC, asthma
Ex.car organs
constipation
BC AVB
Proarrhythmia, CO-

39. USMLE-STEP 1
A 57-year-old man is brought to the emergency room for a suspected myocardial infarction. An electrocardiogram indicates the appearance of a wide-complex ventricular tachycardia with a rate of 126 beats per minute. The physician prescribes a drug to decrease SA node automaticity, increase AV node refractoriness, and decrease AV node conduction velocity. Which of the following agents was most likely prescribed?
A. Amiodarone
B. Disopyramide
C. Lidocaine
D. Propranolol
E. Verapamil