Antiarrhythmic Drugs

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Cardiovascular Drugs in Veterinary Medicine

• Antiarrhythmic Drugs
• Control impulse formation and propagation in
  heart
• Diuretic Drugs
• Change blood volume and ionic composition
• Increase urine formation change urine
  composition
• Heart Failure
• Decrease cardiac loading
• Reduce blood volume
• Decrease peripheral resistance to cardiac
  outflow
• Increase cardiac pumping efficiency

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Antiarrhythmic Drugs (AARDs)
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Cardiac Conduction Pathways
SA node
AV node
Bundle of His- Purkinje fiber system
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Ionic Basis for Action Potentials in SA and AV
Nodes
Phase 4 Diastole with slow depolarization of
membrane potential due to cation (predominately
Ca2? ) leaks across cell membrane ? contributes
to automaticity (formation of electrical
impulses) esp. in SA node. Phase O AP rise due
to ???Ca2? influx Phase 1 Difficult to
define Phase 2 Closing of Ca2 channels Phase 3
Repolarization of cardiac cell back towards
original resting membrane potential due to
opening of K channels
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Automaticity

• Due to slow cation conductance during phase 4
• Slope of phase 4 is indicative of the rate of
  depolarization and AP generation
• Nodes depolarize faster than heart muscle and
  bundle of His (pacemaker hierarchy)

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Pacemaker Hierarchy
1. SA node 2. AV node 3. Bundle of His 4.
Ventricular muscle
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Action Potential Profile in SA and AV Nodes
SA node AV node (both under neuromodulatory co
ntrol)
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Ionic Basis for Action Potentials in Myocardium
and Bundle of His
Phase O Rapid AP rise due to fast?Na?
influx Phase 1 Slight decrease in AP due to
transient outward K current and closure of some
Na channels Phase 2 Plateau phase produced by
opening of Ca2 channels Phase 3 Repolarization
of cardiac cell back towards original resting
membrane potential due to closure of Ca2
channels and opening of several different K
channels Phase 4 Diastole with slow
depolarization of membrane potential due to
cation leaks across cell membrane
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Action Potential Profile in Myocardium and Bundle
of His
Atria Ventricles Bundle of His
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Effective Refractory Period (ERP)

• Minimum time interval between two APs
• The period of time from the upstroke of the
  cardiac AP until tissue excitability is restored
  (tissues cannot conduct impulses during ERP)
• Prevents premature excitation of cardiac tissue
• Depends upon the number of activatible Na
  channels
• Increases proportionately with AP duration

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Neuromodulation of Heart Rate and Conduction

• Location of autonomic nerves containing
• ACh Nodes, atria
• NE Nodes, atria, ventricles
• Automaticity
• ACh/M2-mAChR ? pacemaker current (If) ????sinus
  rate
• NE/b1-AR ? pacemaker current ????sinus rate
• Impulse conduction
• ACh /M2-mAChR
• ATRIA ? AP repolarization rate
  ????ERP,???conduction velocity
• AV NODE ??conduction velocity
• NE /b1-AR
• AV NODE ? conduction velocity
• HIS BUNDLE ? ERP ????automaticity
• ARs may also mediate changes in coronary blood
  flow and plasma K ??D?conduction

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Automaticity, Impulse Conduction and the EKG
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Electrocardiogram - I
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Electrocardiogram - II
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Common Automaticity Disorders
Sinus tachycardia Sinus bradycardia Ectopic
pacemakers
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Common Disorders in Impulse Conduction

• Atrioventricular block (AV block)
• Impulse re-entry
• In AV node, a common cause of supraventricular
  tachyarrhythmias
• In atria, can contribute to fibrillation or
  flutter
• In ventricles, can lead to dangerous ventricular
  tachyarrhythmias progressing to fibrillation
• Atrial fibrillation or flutter
• Ventricular arrhythmias

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AV Block

• Incomplete intermittent or complete (1, 2, 3)
• Complete AV block can result in dissociation in
  atrial and ventricular rates
• As long as ventricles are contracting at their
  own pace, animal will live
• Muscarinic cholinergic antagonists like atropine
  can ? AV block.

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ECG Signs of AV Block
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ECG Signs of Atrial Arrhythmias
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ECG Signs of Ventricular Arrhythmias
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Causes of Cardiac Arrhythmias

• Autonomic nervous system disorders
• Altered ionic permeability of cardiac membranes
• Factors trauma hypoxia infection metabolic
  disease drugs and toxins
• Results in partial or total depolarization in a
  specific area ("injury current")
• Intrinsic cardiovascular disease

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Clinical Considerations in Use of AARDs

• Identify precipitating cause (if possible)
• Establish treatment goals (asymptomatic patients
  risk-benefit analysis)
• Treatment options
• Choice of AARD
• Non-pharmacological interventions
• Minimize treatment risks
• Arrhythmogenic actions of AARDs
• Contraindications (patient variables other drugs)

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AARDs General Mechanisms of Action

• Change gating properties of cardiac ion channels
  (Na, Ca2, K) directly
• Change neuromodulatory control of cardiac ion
  channel opening/closing

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AARDs Blocking Cardiac Ion Channels

• Class I (local anesthetics) Na channels
• Class III (bretylium, amiodarone, sotalol) K
  channels (among other things!)
• Class IV (diltiazem, verapamil) Ca2 channels

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AARDs and Ion Channel Gating
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Class I Na channel blockers

• Three subclasses (A, B and C)
• Based on binding kinetics to Na channels
• Antiarrhythmic action
• They slow the rate of AP rise ????AP duration
  and???conduction in atria (quinidine) or
  His-Purkinje fibers and ventricles (quinidine,
  procainamide, lidocaine)
• pH and ionic balance
• Hypokalemia/alkalosis ????RMP (more negative) in
  cardiac cells ?? less "blockable" Na channels
  ??? drug efficacy
• Hyperkalemia/acidosis/tissue injury ???RMP (less
  negative) ?? more "blockable" Na channels ?
  ??drug efficacy?
• Anticholinergic effects (quinidine gt
  procainamide)

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Class III K channel blockers

• Antiarrhythmic action
• Complex array of actions, but they all block K
  channels
• They slow repolarization (phase 3) of membrane
  potential and ? AP duration ? ? CONDUCTION IN
  VENTRICLES
• "Pure" K channel blockers under investigation
  for AARD activity

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Class IV Ca2 channel blockers

• Diltiazem and verapamil only
• Antiarrhythmic action
• They reduce Ca2 entry in Phase 0 of nodal AP ?
  ? AV nodal conduction

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AARDs Affecting Cardiac Neuroregulation

• Class II (propranolol) block ?-adrenergic
  receptors
• Class V (digitalis glycosides) increase vagal
  (acetylcholine) tone

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Class II ?-Adrenergic Antagonists

• Antiarrhythmic action
• Decrease ?1-AR-mediated effects of NE and E in
  heart
• Decrease sinus rate
• Decrease AV nodal conduction
• Decrease ectopic automaticity in bundle of His or
  ventricles
• Prolong ERP in His bundle, ventricles
• b-AR selectivity
• Propranolol (b1- and b2-ARs)
• Atenolol (b1-ARs only)

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Class V Digitalis (digoxin)

• Antiarrhythmic action
• Stimulate ACh release from cardiac vagal nerves
• Decrease AV nodal conduction
• Not first-line AARD
• AARD action may be beneficial in patients with
  chronic heart failure

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Contraindications to AARDs

• Myocardial contractility (negative inotropic
  effect)
• Hypotension (vasodilatory effects)
• Arrhythmogenesis (some AARDs can ??conduction
  velocity of normal tissue)

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Therapeutic Effects ofAntiarrhythmic Drugs
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Sinus tachycardia

• Class II
• Reduce sympathetic influences on SA node
• Class IV
• Decrease Ca2 influx into SA node ? slower AP
  formation
• Class V
• Increase vagal ACh release ????sinus rate

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Ectopic Pacemakers in Purkinje Fibers

• Class I
• Reduce frequency of AP formation by slowing rate
  of Na influx in phase O
• Class II
• Reduce arrhythmogenic actions of epinephrine on
  Purkinje fibers
• Class III
• Increase ERP in Purkinje fibers by slowing K
  efflux ? slowed phase 3 of AP

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Atrial Flutter/Fibrillation

• Class I (esp. quinidine)
• Block phase O Na entry ? ? atrial ERP and slow
  conduction

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Supraventricular Tachyarrhythmias

• Class II
• Reduce adrenergic influence on AV conduction ?
  slow AV conduction and abolish re-entry
• Class IV
• Decrease Ca2 conductance in AV node ? slow AV
  conduction and abolish re-entry
• Class V
• Increase release of ACh ? slow AV nodal conduction

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Ventricular Arrhythmias

• Class I
• Reduce Na current in phase O ????AP duration
  ??slow conduction velocity ? abolish re-entry
• Class II
• Block adrenergic influence in His-Purkinje system
  ????ERP ? abolish re-entry
• Class III
• Block K current during phase 3 ????ERP ? abolish
  re-entry

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Prototypic AARDs
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Class IA AARD Procainamide

• Cardiac rhythm
• Prolongs ERP and slows conduction in His-Purkinje
  system
• Used for treatment of severe ventricular
  arrhythmias (dogs, horses)
• Used for long-term suppression of premature
  ventricular contractions (dogs)
• Newer AARDs (mexilitene, sotalol) are more
  effective

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Class IA AARD Procainamide

• Pharmacokinetics
• Oral or parenteral administration
• Little plasma protein binding
• Undergoes hepatic N-acetylation (variations in
  dogs)
• Toxicosis
• GI disturbances
• Proarrhythmogenic effects
• Hypotension (rapid i.v. bolus)

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Class IB AARD Lidocaine

• Cardiac rhythm
• Decreases automaticity in damaged Purkinje fibers
• Slows conduction in diseased (i.e. partially
  depolarized) Purkinje fibers and ventricles
• Used exclusively for treating ventricular
  tachyarrhythmias that may lead to VF or reduced
  C.O. (dogs also cats and horses).

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Class IB AARD Lidocaine

• Pharmacokinetics
• Used i.v. in emergency situations
• Moderate to high binding to plasma proteins
• Metabolized in liver (extensive first-pass
  metabolismby p.o. route)
• Excreted in urine
• Toxicosis
• CNS excitation leading to seizures
• Proarrhythmogenic effects

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Class II AARD Propranolol

• Cardiac rhythm
• Blocks both ?1 and ?2 adrenoceptors.
  Cardioselective ?1-adrenergic antagonists like
  atenolol are indicated in patients with reduced
  respiratory reserves
• Decreases SA nodal automaticity (slows sinus
  tachycardia)
• Decreases AV nodal conduction
• Decreases ectopic automaticity in Purkinje fibers
  or ventricles due to disease or drug toxicity.
• Used to suppress supraventricular
  tachyarrhythmias (caused by AV nodal re-entry)
• Can suppress ventricular arrhythmias alone or in
  combination with some Class I AARDs.

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Class II AARD Propranolol

• Pharmacokinetics
• Extensive first-pass metabolism after p.o.
  administration. Can be given by slow i.v.
  infusion.
• High plasma protein binding
• Metabolized in liver, excreted in urine
• Toxicosis
• Bradycardia, hypotension

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Class IV AARD Diltiazem

• Cardiac rhythm
• SA node decreased automaticity. NE reverses its
  negative chronotropic effects ? normal sinus rate
  in healthy patients
• AV node slows conduction ? abolishes re-entry
• Used to treat supraventricular arrhythmias and
  reduce ventricular response to supraventricular
  arrhythmias
• Improves coronary blood flow
• Less negative inotropic effects than verapamil
  (an older drug)

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Class IV AARD Diltiazem

• Pharmacokinetics
• Can be given p.o. or i.v.
• High plasma protein binding
• Excreted in urine
• Toxicosis
• Hypotension
• AV block
• Bradycardia
• Decreased cardiac output ? acute heart failure

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What AARDs Might You Choose?

• Bradyarrhythmias
• Sinus bradycardia
• SA nodal dysfunction
• AV block
• Tachyarrhythmias
• Sinus tachycardia
• Atrial flutter
• Supraventricular tachycardia
• Ventricular PVCs

• What type of tissue is causing the arrhythmia?
• Fast-response (conducting impulses)
• Slow response (normally, SA node generating
  impulses AV node conducting impulses)
• What ion channels may be involved?
• Would arrhythmia be due to an imbalance in
  neuroregulation?