Escolar Documentos
Profissional Documentos
Cultura Documentos
of Arrhythmias
Gaetano M. De Ferrari, M.D.
Channel Channel
closed open
Myocytes
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
Na+ channel
blocked by
Na+ Na+ Class 1 drug
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
Acute Trigger
( phyisical/mental stress)
Smoking cessation
Regular exercise -blockers
Behavior modification
simpathetic tone
-blockers
Time (sec)
Class III Antiarrhythmic Drugs
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
AV node action
Membrane
potential potential
(mV)
Time (sec)
Class IV Antiarrhythmic Drugs
Mechanism
Critical
Components
Vulnerable
Parameters(s)
Target
Intervention Intervention
Result Result
Bundle Branch Reentry Ventricular Tachycardia
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
Triggered Activity
DAD
Mechanism of Delayed Afterdepolarizations
Ionic basis of APD prolongation and EADs
Reentrant
impulse
l Wavelength
ERP Effective refractory period
Conduction velocity
Requirements for Induction
of Reentry
trigger
WL = CV * RP
(mm = mm/s * s)
EG = CL -WL
EG ≤ 0 (mm = mm - mm)
circuit extinction
Bepridil
Verapamil
Diltiazem
Bretylium
Sotalol
Amiodarone
Alinidine
Nadolol
Propanolol
Atropine
Adenosine
Digoxin
Are antiaarrhythmic agents still useful ?