Classification of antiarrhythmic drugs
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Transcript of 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
Ch
ann
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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