Classification of antiarrhythmic drugs

The Sicilian GambitA New Approach to the

Classification of Antiarrhythmic Drugs

ByM.H.Farjoo

Shahid Beheshti University of Medical Science

Advantages of old classification

• Based on physiology• Learned quickly• Facilitates discussion about drugs

& their effects

• Incomplete• Just based on Receptor & Ion blockade• Argues majorly about normal tissue • It is hybrid :

– Some drugs in several classes– Some effects by several mechanisms– Incomplete consistency among drug

effects and it,s target

Disadvantages of old classification

New classification• Based on a

constellation of : drug effects , involved mechanisms & Vulnerable parameters

• Classifies drugs with different effects based on their mechanisms

• Expandable

• Links drug design to arrhythmogenic mechanisms

• Education becomes mechanism based

• Reconciles basic and clinical science

• Encourages understanding of mechanisms

Drug targets

• Ion channels• Pumps• Carriers• receptors

Ion channels • Isoforms• Rectifier• Gating • Gating kinetics• States of channels• Dependency• Intramembrane similarity• Inward & outward

• INa – Causes AP in Atria &

Vent.– Not present in SA & AV

Inward currents of Ion channels

• ICa – ICa-L

• Causes AP in SA & AV• Maintains plateau in

myocardium– ICa-T

• Activates between INa & ICa-L

• Helps to late stages of phase 4

• Involved in abnormal automaticity of atria

• If– non specific channel– Carried by Na– Exists in SA & AV– Causes phase 4 of AP

• INs– non specific channel– Carried by Na– Activated in Ca

overload– Predisposes to DAD

InwardOutward

• IK(Ach) or IK(Ado)

– Inactive during depol.

– inward rectification

– Activated via M2 or Adenosine receptor

• IK(ATP)

– Blocked by ATP– Activated in

ischemia– Shortens AP in

ischemia

• Ik (delayed rectifier)– Main repolarizing

current– By slow kinetic

channel

• IK1 (inward rectifier)– Keeps RMP near

Ek

– Inactive during depolarization

Outward currents of Ion channels

pumps

• Na/K ATPase– Blocked by digital– Regulated via phos. by adrenergic sys.– Produces outward current (INa-K pump)

• Calcium

carriers

• Na/Ca counter transport– Exchanges 3 Na for 1 Ca– Main route of Ca efflux– Current direction depends on Na/Ca

gradient • Na/H exchanger• Cl/Hco3 exchanger• Na/K/Cl cotransport

receptors• β adrenergic

– On ICa-L : EAD & DAD– On If : increases rate of

impulse generation – On IK :accelerates repol.

• Muscarinic – Affects CAMP dependent

currents eg : If , ICa-L , IK

• Purinergic– Similar to muscarinic

Drug-channel interaction• blocking effect of drugs are often Intermittent• Tonic block• Phasic block• Use dependency

– AP duration – Number of activation– Role of Voltage

• Fraction of available Na channels• Direct effect on drug ionization !!• Beneficial effect of voltage dependency in pathologic states

• Reverse Use dependency• Drug effect on refractory period is rate dependent

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Arrhythmogenic mechanisms• What is vulnerable period?• Enhanced normal automaticity• Abnormal automaticity• Reentry• Triggered activity

– EAD– DAD

Enhanced normal automaticity

• Generated by If• Because of change in:

– Max. diastolic potential– Slope of phase 4 of AP– Threshold potential– Duration of AP

• Mechanism of: – Sinus tachycardia– Accelerated idioventricular rhythm

• V.P. is phase 4 of AP

Abnormal automaticity• Spontaneous pulses in partially depolarized

tissues• Depends on different ionic currents in different

levels of depolarization • Seen in:

– Ectopic atrial tachycardia– Accelerated idioventricular rhythm– Post MI V-tach.

• V.P. is decrease in Max. diastolic potential or RMP

• Responds to K channel stimulation [eg:IK(Ach)]

Reentry• Preconditioning factors:

– Existence of obstacle– Pathway length > wavelength– Unidirectional block (Anisotropy)

• Nature of fibrilation• Methods of termination:

– Premature activation – Overdrive pacing– Drugs

• V.P. is conduction and/or refractory period

EAD• Caused by any factor that delays repolarization:

– decrease in normal repolarizing current– Prolongation 0f inward Na & Ca currents– Both of the above

• Often occurs in slow heart rate • Arises from plateau• May lead to “Torsade de pointes”• V.P. is prolonged AP• Responds to increasing heart rate , β receptor

stimulation , hyperkalemia , AP shortening drugs

DAD

• Caused by calcium overload– Digital toxicity– Myocardial Ischemia– Catecholamine excess

• Often occurs in fast heart rate• Arises from RMP• V.P. is calcium overload• Responds to Ca channel blocker , agents

that increase outward current (potassium)

Closing thoughts • An event can be arrhythmogen in a

given rate and antiarrhythmic in another

• “Fast on” drugs prevent , and “Slow on” drugs terminate tachyarrhythmia

• AP prolonging drugs– exert their maximal effect at slow rates – their effect diminishes by increasing rate– May cause EAD– Are antifibrillatory