Transcript Antiarrhythmic Agents

-
Antiarrhythmic Agents
-
AV node
Normal heartbeat and atrial arrhythmia
Normal rhythm
Atrial arrhythmia
AV septum
0
1
2
3
4
Determination of pacemaker rate
-
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 slope:NEP, 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.
-
Abnormalities of Cardiac Impulses
atrial fibrillation
Ventricular fibrillation (VF)
Ventricular tachycardia (VT)
Wolff-Parkinson-White syndrome
Supraventricular tachycardias (SVT)
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
Summary of Antiarrhythmic
classes
Contraction of
ventricles
ECG (EKG): wave segments
IC
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
IA
III
II
IV
-
Cardiac arrythmias





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….
-
Cardiac Electrophysiology


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
-
Determination of pacemaker rate





-
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 slope:NEP, 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.
-
Factors that may precipitate or
exacerbate arrhythmias










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
-
Factors that can increase
automaticity:





hypokalemia
cardiac fiber stretch
beta-adrenergic receptor activation
injury currents
acidosis
Antiarrhthmic Drug
Classes
-
Antiarrhthmic Drug Classes

Class I: Sodium Channel Blockers:





Class II: Beta-Adrenergic Antagonists:



Propranolol
Esmolol
Class III: K+ Channel Blockers:




Disopyramide
Procainamide
Quinidine
Mexiletine
Amiodorone
Dofetilide
Ibutilide
Class IV: Ca+ channel blockers


Diltiazem
Verapamil
-
-
Antiarrhthmic Drug Classes

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.
-
Quinidine: Metabolism


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
-
Amiodarone (Cordarone) (Class I
and III Channel Blocker)
-
Amiodarone



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-ParkinsonWhite syndrome)
-
Amiodarone




Vascular Effects
Noncompetitive a and b adrenergic
receptor blocker
Systemic vasodilation
Antianginal properties, secondary to
coronary vasodilation
-
Amiodarone



Approved for use only in treatment of
serious ventricular arrhythmias (USA)
also used for refractory supraventricular
arrhythmias
Numerous adverse effects.
-
Amiodarone





Metabolism & Excretion
Long elimination halftime: 29 days
Minimal renal excretion
Extensive protein binding
Amiodarone concentrated in the
myocardium (10-50 times plasma
concentration)
-
Amiodarone: Side

Effects
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.
Class II: Beta-Adrenergic
Antagonists





Class II Antiarrhythmic drugs
Propranolol (Inderal)
Metoprolol (Lopressor) (beta-1 "specific")
Pindolol (Visken) (partial agonist)
Esmolol (Brevibloc)(very short acting)
-
-
Class III: Potassium Channel
Blockers
-
Bretylium (Bretylol)
-
Class IV:
Calcium Channel Blockers
Verapamil
Diltiazem & Bepridil
-
Antiarrhthmic Drug Classes




Class I: Sodium Channel
Blockers
Class II: Beta-Adrenergic
Antagonists
Class III: prolongation of AP
Class IV: Ca+ channel
blockers
-
Antiarrhthmic Drug Classes

Class I: Sodium Channel Blockers:





Class II: Beta-Adrenergic Antagonists:



Propranolol
Esmolol
Class III: K+ Channel Blockers:




Disopyramide
Procainamide
Quinidine
Mexiletine
Amiodorone
Dofetilide
Ibutilide
Class IV: Ca+ channel blockers


Diltiazem
Verapamil
THE END