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Pharmacological Therapy

of Arrhythmias
Gaetano M. De Ferrari, M.D.

Dept. of Molecular Medicine, University of Pavia


Dept. of Cardiology and
Cardiovascular Clinical Research Center -
Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
Ion channels in the heart
Ions move across the membranes of conduction tissue
and the myocytes through voltage controlled ion channels
ION
ION

Channel Channel
closed open
Myocytes

Changes in the membrane potential of the myocytes cause…

Myocytes to contract
Myocytes to pass on action potential to next myocyte (which in turn
contracts… and so on)
This ensures a smooth wave of contraction across the myocardium
Action potential in the myocytes
Action potential in conductive tissue
Vaughan Williams classification
Class Actions Examples
Block sodium channels and delay
repolarisation, thereby increasing the
Ia duration of the action potential.
Quinidine, disopyramide, procainamide
Moderately slow conduction
Block sodium channels and accelerate
Ib repolarisation, thereby decreasing the Lidocaine, mexiletine,
duration of the action potential
Block sodium channels but have little
Ic effect on repolarisation. Depress phase Flecainide, propafenone
0 depolarisation and slow conduction
Block ß-adrenoceptors. Reduce
hyperactivity of the sympathetic
II nervous system and depress phase 4
atenolol, esmolol, metoprolol
depolarisation
Increase the duration of the action
III potential and effective refractory period
sotalol, amiodarone, bretylium

Block calcium channels. Slow


conduction through calcium channel-
IV dependent tissues (e.g. the sinoatrial
Verapamil, diltiazem
and atrioventricular nodes)
VW Class 1 drugs

Na+ channel
blocked by
Na+ Na+ Class 1 drug

Channel closed Channel


Na+
but will respond to refractory and
Channel unresponsive to
depolarisation by
open and depolarisation
opening
Na+ enters
the cell
Na+ channels exist in three states, closed, open and refractory
VW Class I drugs – Ia
Quinidine, disopyramide, procainamide

Class 1a binds most strongly when the Na+ channels are open rather
than closed so are termed “use dependent”, i.e. the more frequently
the Na+ channels open, the stronger is the blocking action

Moderately slow
conduction
Membrane Moderately
potential prolonged action
(mV) potential

Time (sec)
Class IA Drugs Uses
• Class IA drugs are effective in treatment of both
supraventricular and ventricular arrhythmias
• Quinidine rarely used for supraventricular arrhythmias
• Oral quinidine/procainamide have been used with class III
drugs in refractory ventricular tachycardia patients with
implantable defibrillator
• IV procainamide may be used for hemodynamically stable
ventricular tachycardia
• IV procainamide may be used for acute conversion of atrial
fibrillation including WPW syndrome
Class IA Drugs Toxicity
Quinidine Procainamide
• A-V block at higher plasma levels  At high levels, asystole or induction of
ventricular arrhythmias
• At toxic levels, ventricular tachycardia  Hypersensitivity reactions including drug fever
and torsade de pointes ventricular and rarely agranulocytosis.
arrhythmia  Systemic lupus erythromatosus (SLE)-like
• Increasing digoxin plasma (arthralgia, fever & pleural-pericardial
inflammation)
concentration by displacing digoxin  The SLE is dose- and time-dependent, and
from binding sites in addition to usually disappears upon drug stop
decreased digoxin renal clearance  It is most common in patients with slow hepatic
• Cinchonism occurs at large dose levels acetylation resulting in higher plasma level of
(blurred vision, tinnitus, headache, the parent drug
psychosis and gastrointestinal upset) Disopyramide
• 1. Anticholinergic side-effects
• Digoxin is administered before • 2. Induction of ventricular arrhythmias in
quinidine to prevent the conversion of patients with prolonged QT interval
atrial fibrillation or flutter into • 3. Similar to quinidine, disopyramide may induce
paradoxical ventricular tachycardia. ventricular arrhythmia if used alone in the
Quinidine shortens of A-V nodal treatment of fibrillation
refractoriness by atropine-like effects
VW Class I drugs – Ib
Lidocaine & mexiletine
Class 1b drugs such as lidocaine associate and dissociate rapidly from
the Na+ channels.
Class 1b bind preferentially to the Na+ channels in refractory phase,
i.e. when cell is depolarised which occurs especially in ischaemic cells

Minimally slow
conduction
Shortened action
Membrane potential duration
potential
(mV)

Time (sec)
Agents of Class IB
Lidocaine Mexiletine
• It should be used by intravenous • Oral analogs of lidocaine
route because of its extensive • Mexiletine is used for recurrent
first-pass metabolism VTs in patients with ICDs and
• Lidocaine is the drug of choice in depressed LV function (minimal
emergency treatment of effect on contractility)
ventricular arrhythmias

Uses
 They are used in the treatment of ventricular arrhythmias arising during
myocardial ischemia or due to digoxin toxicity
 They have little effect on atrial or AV junction arrhythmias
VW Class 1 drugs – 1c
Flecainide & propafenone
Class 1c drugs associate and dissociate very slowly from the Na+
channels. Little preference for refractory channels so not specific for
damaged ischaemic cells. Gives general reduction in excitability and
can suppress re-entrant rhythms. Conduction through the Bundles of
His and Purkinje fibres is inhibited, thus prolonging QRS complex

Markedly slow
conduction
Minimally prolonged
Membrane action potential
potential duration
(mV)

Time (sec)
Class IC Drugs
• Agents of Class IC: Flecainide & propafenone
• Uses:
 They are broad-spectrum but only approved in the US for
refractory ventricular arrhythmias
 Flecainide is a particularly potent suppressant of premature
ventricular contractions
• Toxicity and Cautions for Class IC Drugs:
 They are severe proarrhythmic drugs causing severe worsening
of a preexisting arrhythmia or de novo occurrence of life-
threatening ventricular tachycardia
 In patients with frequent PVCs following MI, flecainide increased
mortality compared to placebo
Notice: Class 1C drugs are particularly of low safety and have
shown even to increase mortality when used chronically after MI
Beta-blockers
Beta-blockers are antagonists for β-adrenergic receptors on the heart
that respond to adrenaline and the neurotransmitter noradrenaline

Adrenergic (sympathetic)
neuron terminal

noradrenaline Beta-blocker

b1-adrenergic receptor

Myocyte or conductive tissue


Class II ANTIARRHYTHMIC DRUGS
(β-adrenergic blockers)
Uses
β-Adrenergic blockers • They are used in treatment
produce both negative of increased sympathetic
inotropic & chronotropic activity-induced
effects arrhythmias such as stress-
• They diminish phase 4 and exercise-induced
spontaneous arrhythmias
depolarization suppressing • Treatment of atrial flutter
automaticity and and fibrillation
prolonging AV conduction
• AV nodal tachycardia
Triggers of Acute Cardiac Events
Coronary Atherosclerosis
Plaque stabilization

Acute Trigger
( phyisical/mental stress)
Smoking cessation
Regular exercise -blockers
Behavior modification
 simpathetic tone
-blockers

 mechanical  Hemodinamic  Risk of Electrical


forces factors( HR,  BP, thrombosis ( Plat. Aggreg. instability
( shear stress  contractility)  fibrinolysis)
vasospasm)
-blockers -blockers
Antiplatelets Rx ? AAD
-blokers antithrombosis

Vulnerable Plaque Acute IM SCD


plaque disruption
Lipid lowering drugs ACE-i
ACE-i
Muller et al. Circulation 1997; 96:3233-3239
Class II Antiarrhythmic Drugs

• Propranolol: was proved to reduce the incidence of


sudden arrhythmatic death after myocardial infarction
• Metoprolol & Pindolol
 Metoprolol and other selective β1-adrenergic blockers
reduce the risk of bronchospasm
 Pidolol, having additional partial agonistic activity, may
decrease the frequency of cardiac failure
• Esmolol:
 Esmolol is a very short-acting β1-adrenergic blocker
that is used in the by intravenous route in acute
arrhythmias occurring during surgery or emergencies
VW Class III drugs
Class III drugs extend the duration of the action potential mostly by
blocking one or more of the K+ channels involved in repolarisation

Membrane Prolonged action


potential potential duration
(mV)

Time (sec)
Class III Antiarrhythmic Drugs

• Class III antiarrhythmic drugs prolong phase 3


depolarization, without altering phase 0
upstroke or the resting membrane potential
• They prolong both the duration of the action
potential and the effective refractory period
(ERP)
Class III Antiarrhythmic Drugs
• Drugs of Class III:
Sotalol, bretylium, amiodarone, ibulitide
• Uses:
They are used in the treatment of ventricular
arrhythmias, especially ventricular fibrillation or
tachycardia
Supra-ventricular tachycardia
Amiodarone usage is limited by its wide range
of side effects
Class III Antiarrhythmic Drugs
Sotalol
• Sotalol is a β-adrenergic blocker that also prolongs the duration of
action potential and refractoriness in all cardiac tissues
• Sotalol suppresses Phase 4 spontaneous depolarization and possibly
producing severe sinus bradycardia
• The β-adrenergic blockade combined with prolonged action
potential duration may of special efficacy in prevention of sustained
ventricular tachycardia
• It may induce the polymorphic torsade de pointes ventricular
tachycardia
Bretylium
• It is generally administered parenteraly because of poor GIT
absorption
• Long-term oral use is associated with painful parotid enlargement
as well as severe postural hypotension
Class III Antiarrhythmic Drugs
Amiodarone
• Amiodarone is a drug of multiple actions and not well understood
• It is extensively taken up by tissues, especially fatty tissues, and has a half-life of up
to 60 days
• Amiodarone antiarrhythmic effect is complex comprising class I, II, III, and IV
actions
• Prolongation of action potential duration and refractoriness is the main
• It slows cardiac conduction, works as Ca2+ channel blocker, and as a weak β-
adrenergic blocker
• Amiodarone Toxicity
 Amiodarone has wide-spectrum toxicity
 Most common include GI intolerance, tremors, ataxia, dizziness, hyper-or
hypothyrodism
 Corneal microdeposits may be accompanied with disturbed night vision
 Other common side effects include liver toxicity, photosensitivity, gray facial
discoloration, neuropathy, muscle weakness, and weight loss
 The most dangerous side effect is pulmonary fibrosis which occurs in 2% of the
patients
Characteristics of dronedarone
 Multi-channel blocker
 Class I-IV Vaughan-Williams properties
 Iodine removed in order to improve thyroid safety
 Methylsulfonamide group added to reduce lipophilicity

O C4H9
CH3SO2NH O (CH2)3 N
C4H9

O C4H9

Dronedarone (MW=593)
Pharmacology of Dronedarone
• Well absorbed after oral administration
• ~ 15% bioavailability (non-fasting)
– Cmax increased 2–3 fold when given with food
• highest bioavailability with high-fat meal
• Highly metabolized, mainly by CYP 3A4
• Excretion in the feces (probably through biliary excretion)
• tmax ~ 3–6 hours
• t1/2: 27–31 h
• Slight increase in creatinine (15%) due to inhibition of
tubular secretion
VW Class IV Drugs
Verapamil & diltiazem

Class IV drugs such as Verapamil exert their action by


blocking voltage dependent Ca2+ channels especially in the
atrio-ventricular node

AV node action
Membrane
potential potential
(mV)

Time (sec)
Class IV Antiarrhythmic Drugs

Verapamil and diltiazem bind only to open depolarized


voltage-operated Ca2+ channels, and hence preventing re-
polarization until the drug dissociates from the channels.
Therefore, they are use-dependent blocking rapidly beating
heart since in a normally-paced heart, Ca2+ channels have
enough time to repolarize and the drug to dissociate from
the channel before the next conduction cycle
Verapamil and diltiazem slow conduction and prolong
effective refractory period in Ca2+ current-dependent
tissues like AV node
Class IV Antiarrhythmic Drugs
Verapamil & diltiazem are more effective in treatment of atrial
than ventricular arrhythmias.
They are used in treatment of supra-ventricular tachycardia
preventing the occurrence of ventricular arrhythmias
They are used in treatment of atrial flutter and fibrillation
Both drugs are contraindicated patients with pre-existing
depressed heart function because of their negative inotropic
activity
Both drugs may cause bradycardia, and asystole especially
when given in combination with β-adrenergic blockers
Miscellaneous Antiarrhythmic Drugs
Adenosine
Adenosine activates A1-purinergic receptors decreasing
the SA nodal firing and automaticity, reducing conduction
velocity, prolonging effective refractory period, and
depressing AV nodal conductivity
It is the drug of choice in treatment of paroxysmal supra-
ventricular tachycardia
It is used only by slow intravenous bolus
It has only low-profile toxicity being ultra-short acting of 15
seconds duration
Possible Approaches to the Evaluation
of Antiarrhythmic Drug Action
GAMBIT EMPIRIC
Arrhythmia Arrhythmia

Mechanism

Critical
Components

Vulnerable
Parameters(s)

Target

Intervention Intervention

Result Result
Bundle Branch Reentry Ventricular Tachycardia

Bundle Branch Reentry

His Bundle

Left Bundle
RBB Branch

500 ms
Mechanisms of cardiac arrhytmhias

Focal mechanisms
• Automaticity (enhanced normal or abnormal)
• Triggered activity (due to EAD or DAD)

• Reentry

• Combination of both focal mechanisms and reentry


Diagram of delayed afterdepolarization

Triggered Activity

DAD
Mechanism of Delayed Afterdepolarizations
Ionic basis of APD prolongation and EADs

Inward (ICa INa)

Outward (Ito IK)


K channels and repolarization
Possible Reentry Mechanism

Reentrant
impulse

Wit AL, Rosen MR, Hoffman BF. Am Heart J 90:397, 1975


Diagram of Reentry Caused by
Dispersion in Refractory Periods
Reentry: Electrophysiological bases
reentrant
l = ERP x  circuit

l Wavelength
ERP Effective refractory period
 Conduction velocity
Requirements for Induction
of Reentry
trigger

unidirectional block exctitable gap


(prevents wavefronts collision) (non-refractory tissue)

trigger unidirectional block excitable gap


Excitable Gap and Circuit Wavelength
EG >0
(circuit perpetuation)

WL = CV * RP
(mm = mm/s * s)

obstacle size > WL

EG = CL -WL
EG ≤ 0 (mm = mm - mm)
circuit extinction

obstacle size <WL


Sicilian Gambit Classification of AA Drugs
Channels Receptors Pumps
+
High Drugs Na
Ca K If a  M2 A1
Na/K
1 2 3 ATPase
Medium
Lidocaine
Low Mexiletine
Tocainide
Moricizine
Procainamide
Agonist/antagonist Disopyramide
Quinidine
Agonist Propafenone
Flecainide
Encainide

Bepridil
Verapamil
Diltiazem

Bretylium
Sotalol
Amiodarone

Alinidine

Nadolol
Propanolol

Atropine

Adenosine

Digoxin
Are antiaarrhythmic agents still useful ?

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