Antiarrhythmic drugs work by targeting ion channels to control arrhythmias. They are classified based on their electrophysiological effects. Class I drugs prolong the refractory period. Class II drugs are beta blockers. Class III drugs prolong action potential duration. Class IV drugs block calcium channels. The ideal drug would work for all arrhythmias safely but in reality, drugs can paradoxically cause arrhythmias. Careful matching of drug to arrhythmia type is needed due to the narrow therapeutic window.

1. Antiarrhythmic drugs…
an overview
Peter Light
Assistant Professor
Dept of Pharmacology

2. Arrhythmias
• Disturbances in ionic homeostasis
can trigger arrhythmias
• May be caused by genetic defects,
ischemia, drugs and hormones
• Ion channels control ionic balance and are
therefore good targets for antiarrhythmic drugs

3. What is an arrhythmia?
Fatal ventricular fibrillation leading to death

4. Arrhythmias
• Treatment of the underlying disease
e.g. CHF, mitral disease, WPW
• Cardioversion (defibrillator)
• Drugs
There is no real “magic bullet”

5. Treating arrhythmias….
• Surgical intervention
• Implantable pacemakers
and defibrillators
• Drugs

6. Ion Flow and the Action Potential
Na + Ca 2+ K+
(140 mM) (1.8 mM) (5 mM)
outside
inside
Na + Ca2+ K+
(5 mM) (100 nM) (140 mM)
Depolarizing Repolarizing

7. depolarizing
Ion channels
and the
Action potential
repolarizing

8. Antiarrhythmic drugs: Ideal properties
• Good for all types of arrhythmia
• Prevent reentry (one-way to two way block)
• Increase refractory period
• Block the effects of catecholamines
• Reduce excitability
• Little or no effects on contractility (inotropy)
• Use-dependent block

9. The reality of anti-arrhythmic drugs
• Must match the type of drug to the type of arrhythmia
• The paradox: in the wrong circumstance drugs
may actually trigger arrhythmias
• “Therapeutic window” in many patients is small

10. Vaughan-Williams Classification
Of Anti-arrhythmic Drugs
Four main classes based on in vitro
Electrophysiological Effects
Atria, Purkinje fibre
ventricle
Fast AP
SA/AV nodes
Slow AP

11. Class 1 Anti-arrhythmics
CLASS 1A "Membrane stabilizers which prolong refractory period"
CLASS 1B "Membrane stabilizers which reduce refractory period“
CLASS 1C "Membrane stabilizers which slow depolarization”
Class 1A e.g. Class 1B e.g. Class 1C e.g.
Quinidine Lidocaine Encainide
Procainamide Phenytoin Flecainide
Dysopyramide Mexiletine (rarely used now)

12. Class 1A Typical example: - Quinidine
In the whole heart this leads to:
• decreases in conduction velocity
• decreases in automaticity
• increases in refractory period
• increased Q-T interval
• conversion of one way block to two way block
(abolishes re-entry)
• increasing degree of block with more activity
• decreases in contractility (negative inotropic effect)
Used in atrial flutter/fibrillation. Nowadays class III agents are preferred as
Quinidine has many side effects.

13. Class 1B Typical example: Lidocaine
Direct Effects on Cardiac Myocytes
• blocks Na+ channels..increase threshold
• only slows rate of rise of Phase 0 in damaged tissue
(use-dependent effect)
Important…….
Use-dependence: The blocking action of the drug is more potent
when ion channels are open ie. When more APs are firing.

14. Use dependence
lidocaine
lidocaine

15. Class 1B Typical example: Lidocaine
In the whole heart this leads to:
• decreases in automaticity especially in Purkinje Fibres
• different effects on ischemic tissue vs healthy tissue
• conversion of one way block to two way block in ischemic tissue
• decreased APD (action potential duration) and ERP
(effective refractory period).
• little effect on contractility
• little effect on ECG of healthy patients
• good in acute situations eg. lidocaine in post-MI
• good for ventricular arrhythmias but NOT supraventricular
• short ½ life ~ 20 mins

16. CLASS IC Anti-arrhythmics
"Membrane stabilizers"
eg. Encainide, Flecainide.
•Little “use dependence”
•Bind more tightly, reaching a steady-state level
•General reduction in excitability
•Occasionally used for atrial fibrillation and tachycardias
with abnormal conducting pathways
•Not recommended post MI
•To be used with discretion and can be pro-arrhythmic

17. CLASS II Anti-arrhythmics
"Anti-adrenergics" (ß-adrenergic antagonists)
eg. Propanolol and Metroprolol
ß blocker and membrane stabilizer
often used as an adjunct to other therapies. SA/AV node
BUT contraindicated in:
• acute heart failure
• asthma (why?)
• arrhythmias with A-V block
Note: Adrenaline can cause arrhythmias through effects on the pacemaker
potential and delayed after-depolarizations. Antagonism of the ß1-receptors
prevents this.

18. CLASS III Anti-arrhythmics
"Prolong APD and ERP, no effect on rise time “
Potassium channel blockers
Can have “reverse use-
dependence”
(with the exception
of amiodarone)
• Action on phase 3 of AP waveform
• Delays repolarization, lengthens APD
• Action on IKR,IKS current K channel sub-types

19. CLASS III Anti-arrhythmics
Example: Amiodarone
• prolongs refractory period
• long duration of action (>30 days)
• drug of choice in prevention of life-threatening
ventricular arrhythmias..prophylactic or acute?
• also used for atrial fibrillation/flutter
• effective but “complex” profile - side effects
Example: Sotalol. ß-Blocker and Class III
Anti-arrhythmic….prolongs APD
Used for severe VT and VF especially if patients can’t
tolerate amiodarone

20. Can lengthen
AP duration
too much!

21. Drugs:
Long QT and TdP

22. Drugs: LQT and TdP

23. Drugs that prolong QT..

24. Drugs that prolong QT..cont

25. Seldane
• Seldane (terfenadine), an anti-histamine
OTC hay fever drug was withdrawn from market in 1997.
Why?
The pro-drug Terfanadine metabolized to the active metabolite fexofenadine by
hepatic CYP3A4 activity (cytochrome P450-3A4).
If CYP3A4 activity is inhibited then terfenadine levels rise. Terfenadine is a very
good inhibitor of IKr (HERG) current in the heart leading to TdP. Many antifungal
and antibiotics inhibit CYP3A4.
The active metabolite fexofenadine
is now marketed as Allegra

26. CLASS 4 Anti-arrhythmics
Eg.Verapamil and Diltiazem
•`cardioselective' Ca2+ channel blockers
•block A-V conduction, useful in supra-
ventricular arrhythmias
• primarily effect SA/AV node APs
- dangerous for ventricular arrhythmias
‘vascular selective' Ca2+ channel
blockers
(ni***dipine/ dihydropyridines)
are better vasodilators –
NOT anti-arrhythmic agents
Dose-selective block of vascular
Calcium channels

27. Other clinically important anti-arrhythmics.

28. Adenosine
• occurs naturally
• electrophysiological effects like ACh
decreases sinus rate; decreases A-V conduction
• useful for supraventricular tachycardias
• also anti-ischemic
• short t1/2
Action of adenosine is through
The A1 receptor directly coupled

29. Cardiac Glycosides
(digitalis glycosides eg.. Digoxin)
Digitalis, a drug prepared from digitalin, a glycoside obtained
from the common foxglove, is used in medicine. With techniques
of modern pharmacology, about a dozen steroid glycosides
have been isolated from the leaves. The best known of these
exert a twofold action on the heart that results in a more
effective heartbeat. These medicines strengthen the force
of contraction and, at the same time, slow the beat so that
the period of relaxation between beats is lengthened. The heart
muscle thus obtains more rest even though it is working harder.
• acting on Na/K exchangers..(increased Nai)
• therapeutic action of digitalis from its ability to
slow A-V conduction via increases in vagal tone
• used for atrial fibrillation
• associated increases in contractility (CHF)

30. Toxicity of glycosides
•Potentially fatal - common
•Difficulty of diagnosis
•Toxic dose = 2-3 x therapeutic dose
•5-25 % of patients exhibit signs of toxicity
•arrhythmias, enhancement of effects seen
with therapeutic dose and generation of
early and delayed afterdepolarizations (EADs
and DADs).
Best treatment is phenytoin (class 1B.)

31. Glycosides and afterdepolarizations