Antiarrhythmic Agents

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Antiarrhythmic Agents

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Normal heartbeat and atrial arrhythmia
Normal rhythm
Atrial arrhythmia
AV septum
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Determination of pacemaker rate

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• 1- more negative maximum diastolic potential,
  from -80 to -100mV Vagal AC-chol. discharge.
• 2- reduction of the slope of diastolic
  depolarization b-Blockers.
• increase slopeNEP, low K, fiber stretch,
  acidosis and injury increase slope
• More positive threshold potential, from -65 to
  -45mV.
• Not common, prolongation of the action potential
  duration.

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Abnormalities of Cardiac Impulses

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Effects of Class IA, IB, and IC antiarrhythmics
on the ventricular action potential
Class I antiarrhythmics (Na channel blockers)
act on ventricular myocytes to decrease re-entry.
All subclasses of the class I antiarrhythmics
block the Na channel to some degree class IA
agents exhibit moderate Na channel block, class
IB agents rapidly bind to (block) and dissociate
from (unblock) Na channels, and class IC agents
produce marked Na channel block. Class IA, IB,
and IC agents also differ in the degree to which
they affect the duration of the ventricular
action potential
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Summary of Antiarrhythmic classes
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Contraction of ventricles
ECG (EKG) wave segments
Repolarization of ventricles
Contraction of atria
Class I Na channel blockers Class II
B-Blockers Class III K channel blockers Class
IV Ca channel blockers
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Cardiac arrythmias

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• Occurs in 25 treated with digitalis
• 50 of anesthetized patient
• 80 of patients with acute myocardial infraction
• Need treatment because
• Too rapid or too slow or asynchronous reduce
  cardiac output.

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Cardiac Electrophysiology

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• Transmembrane potential -- determined primarily
  by three ionic gradients
•  Na, K, Ca 2
•  water-soluble, -- not free to diffuse through
  the membrane in response to concentration or
  electrical gradients depended upon membrane
  channels (proteins)
• Movement through channels depend on controlling
  "molecular gates"
•  Gate-status controlled by
• Ionic conditions
• Metabolic conditions
• Transmembrane voltage

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Determination of pacemaker rate

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• 1- more negative maximum diastolic potential,
  from -80 to -100mV Vagal AC-chol. discharge.
• 2- reduction of the slope of diastolic
  depolarization b-Blockers.
• increase slopeNEP, low K, fiber stretch,
  acidosis and injury increase slope
• More positive threshold potential, from -65 to
  -45mV.
• Not common, prolongation of the action potential
  duration.

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 Factors that may precipitate or exacerbate
arrhythmias

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• Ischemia
• Hypoxia
• Acidosis
• Alkalosis
• Abnormal electrolytes
• Excessive catecholamine levels
• Autonomic nervous system effects (e.g., excess
  vagal tone)
• Drug effects e.g., antiarrhythmic drugs may
  cause arrhythmias)
• Cardiac fiber stretching (as may occur with
  ventricular dilatation in congestive heart
  failure)
• Presence of scarred/diseased tissue which have
  altered electrical conduction properties

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Factors that can increase automaticity

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• hypokalemia
• cardiac fiber stretch
• beta-adrenergic receptor activation
• injury currents
• acidosis

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Antiarrhthmic Drug Classes
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Antiarrhthmic Drug Classes

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• Class I Sodium Channel Blockers
• Disopyramide
• Procainamide
• Quinidine
• Mexiletine
• Class II Beta-Adrenergic Antagonists
• Propranolol
• Esmolol
• Class III K Channel Blockers
• Amiodorone
• Dofetilide
• Ibutilide
• Class IV Ca channel blockers
• Diltiazem
• Verapamil

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Antiarrhthmic Drug Classes

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• Class I Sodium Channel Blockers
• Class IA (effective in treating Sinoatrial
  lessventricular arrhythmias)
• Quinidine
• Procainamide
• Disopyramide.
• Class IB (effective in treating ventricular
  arrhythmias)
• Lidocaine
• Mexiletine
• Tocainidine
• Phenytoin.

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Quinidine Metabolism

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• Hepatic hydroxylation to inactive metabolites
  followed by renal excretion
• 20 excreted unchanged in urine
•  Impaired hepatic/renal function accumulation of
  quinidine and metabolites
•  Sensitive to enzyme induction by other agents--
• decreased quinidine blood levels with phenytoin,
  phenobarbital, rifampin

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Amiodarone (Cordarone)  (Class I and III Channel
Blocker)

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Amiodarone

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• Mechanism of Action
• Blocks sodium and potassium channels and prolongs
  action potential duration.
• Prolongs effective refractory period in
• SA node
• AV node
• ventricle
• atrium
• His-Purkinje system
• accessory bypass tracts (Wolff-Parkinson-White
  syndrome)

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Amiodarone

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• Vascular Effects
• Noncompetitive a and b adrenergic receptor
  blocker
• Systemic vasodilation
• Antianginal properties, secondary to coronary
  vasodilation

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Amiodarone

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• Approved for use only in treatment of serious
  ventricular arrhythmias (USA)
• also used for refractory supraventricular
  arrhythmias
•  Numerous adverse effects.

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Amiodarone

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• Metabolism Excretion
• Long elimination halftime 29 days
• Minimal renal excretion
• Extensive protein binding
• Amiodarone concentrated in the myocardium (10-50
  times plasma concentration)

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Amiodarone Side Effects

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• Pulmonary
• Most serious adverse effect seen in long-term
  therapy is a rapidly progressive pulmonary
  fibrosis which may be fatal
• Frequency 5-15 treated patients
• Mortality rate 5 to 10
• Cause unknown (possibly related to
  amiodarone-mediated generation of free oxygen
  radicals in the lung)
• Two types of amiodarone-pulmonary toxicity
  clinical presentations
•  More common Slow, insidious, progressive
  dyspnea, cough, weight loss, pulmonary
  infiltration (chest x-ray)
•  Acute onset dyspnea, cough, arterial hypoxemia.
  

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Class II Beta-Adrenergic Antagonists

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• Class II Antiarrhythmic drugs
• Propranolol (Inderal)
• Metoprolol (Lopressor) (beta-1 "specific")
• Pindolol (Visken) (partial agonist)
• Esmolol (Brevibloc)(very short acting)

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Class III Potassium Channel Blockers

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Bretylium (Bretylol)

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Class IV Calcium Channel BlockersVerapamilDil
tiazem Bepridil

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Antiarrhthmic Drug Classes

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• Class I Sodium Channel Blockers
• Class II Beta-Adrenergic Antagonists
• Class III prolongation of AP
• Class IV Ca channel blockers

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Antiarrhthmic Drug Classes

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• Class I Sodium Channel Blockers
• Disopyramide
• Procainamide
• Quinidine
• Mexiletine
• Class II Beta-Adrenergic Antagonists
• Propranolol
• Esmolol
• Class III K Channel Blockers
• Amiodorone
• Dofetilide
• Ibutilide
• Class IV Ca channel blockers
• Diltiazem
• Verapamil

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THE END