Pharmacotherapy of cardiac arrhythmias

Pharmacotherapy of
Cardiac Arrhythmia
Dr. Vikas S. Sharma
Dept. Of Pharmacology
GMC, Nagpur
16.02.2016

Overview
• Electrophysiology of cardiac rhythm
• Mechanisms in cardiac arrhythmia
• Classification of anti-arrhythmic drugs
• Treatment of individual arrhythmias
• Summary
Page 2 of 68 Pharmacotherapy of cardiac arrhythmias – Dr. Vikas S. Sharma
16.02.2016

Electrophysiology of cardiac rhythm
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Fast & Slow channel AP
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Mechanism of Cardiac arrhythmias
• Abnormal impulse generation
• After-depolarization
• Delayed after-depolarization (DAD)
• Early after-depolarization (EAD)
• Abnormal impulse conduction
• Conduction block
• Re-entry phenomenon (Circus movement of rhythm)
• Accessory tract pathway
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Abnormal impulse generation
• Depressed automaticity SA node – escape beat & ↓ HR
• Enhanced automaticity SA node - ↑ HR
• AV node , Purkinje fibres, atrial & ventricular cells:
spontaneous diastolic depolarisation & repetitive firing –
RMP - 60 mV
AV nodal rhythm,
idioventricular rhythm or
ectopic beats
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Ectopic activity is encouraged by-
• Faster phase 4 depolarisation
• Less negative resting membrane
potential (RMP)
• More negative threshold potential
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After depolarisation
Normal action potential (AP) triggers
extra-abnormal depolarisation
Abnormal Ca2+ influx into cardiac myocyte
during or immediately after phase 3 of
ventricular AP
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of 68 Pharmacotherapy of cardiac arrhythmias – Dr. Vikas S. Sharma
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Abnormal impulse conduction
A. Conduction block:
• Dropped beat or idioventricular rhythm
• Severely depressed conduction
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B. Re-entry phenomenon:
• 80 – 90 % Clinical arrhythmia
• Re-entrant arrhythmias
Premature beat, paroxysmal supraventricular
tachycardia (PSVT), atrial flutter (AFL) &
ventricular fibrillation (VF)
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Circus movement of rhythm & accessory
tract pathway
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Functional re-entry
• Functional obstacle and unidirectional conduction pathway
is created by a premature impulse
• On encountering refractory tissue in one direction,
wavefront travels through partially recovered fibres—gets
markedly slowed and can set up small re-entry circuits
which may constantly shift location
Ventricular extrasystoles,
polymorphic ventricular tachycardia,
Atrial / Ventricular Fibrillation
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Fractionation of impulse
• When atrial ERP is brief and inhomogeneous, an impulse
generated early in diastole gets conducted irregularly over
the atrium, slowly through fibres with longer ERP (partially
recovered) and not at all through those still refractory
• Asynchronous activation of atrial fibres→ atrial fibrillation
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Classification
I. Membrane stabilizing agents (Na+ channel blockers):
A. Quinidine, Procainamide, Disopyramide
B. Lidocaine, Mexiletine
C. Propafenone, Flecainide
II. Antiadrenergic agents (β blockers): Propranolol,
Esmolol, Sotalol
III. Agents widening AP: Amiodarone, Dronedarone
Dofetilide, Ibutilide
IV. Calcium channel blockers: Verapamil, Diltiazem
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In addition
1. For PSVT : Adenosine, Digoxin
2. For A-V block : Sympathomimetics - Isoprenaline
Anticholinergics - Atropine
3. Digitalis: AF, AFL and PSVT to control ventricular rate
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Class I
• Division: interaction with cardiac Na+ channel &
effect on different phases of cardiac AP
Binds to Na+ channel more strongly when they
are in activated or inactivated state
USE DEPENDENCE
Block high frequency excitation of myocardium without
preventing heart from beating at normal frequency
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Class IA
• Mechanism of action (MoA):
• Extinguish ectopic pacemaker & abolish re-entry by
converting unidirectional block into bidirectional block
Blocks activated Na+ channels > inactivated
channel & slow rate of dissociation
(recovery time 1-10 sec)
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Quinidine
• Also has anti-vagal action
• Depresses myocardial contractility
• ECG - ↑ PR & QT interval & broaden QRS complex
• Side effect –
• Rise in blood levels & toxicity of digoxin
• Dose – 200-400 mg TDS orally
Diarrhoea (MC)
Quinidine syncope
Cinchonism
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Procainamide
• Cardiac electrophysiological action is almost identical to
that of quinidine
• Differences are:
• Long term high dose therapy – SLE
•Less effective in suppressing ectopic automaticity
•Less marked depression of contractility & AV
conduction
•No anti-vagal action
•No α blocking activity
•Doesn’t alter plasma levels of digoxin
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• Dose:
• Uses:
Abolition of arrhythmia:
500 mg iv loading dose (25 mg/min inj.) f/b 2 mg/kg/hr
Or
500 mg oral / im f/b 250-500 mg every 2 hrs
Maintenance dose:
500 mg every 4-6 hrs
To terminate VT & some
supraventricular arrhythmia
Many WPW reciprocal VTs respond
& to prevent recurrence of VF
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Disopyramide
• Prominent cardiac depressant & anti-cholinergic action
• No interaction with digoxin
• Longer T1/2 (6-8 hrs)
• Side effects – anti-cholinergic are most prominent
• Dose – 100-150 mg 6-8 hrly oral
• Uses – 2nd
line drug for prevention of recurrence of
ventricular arrhythmia
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Class IB
• Like quinidine, also abolish ventricular re-entry
tachycardia
• Block inactivated > activated Na+ channels & rapid
rate of association & dissociation
• Do not delay channel recovery (recovery time < 1 sec)
• Block Na+ channels more in diseased myocardium
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Lidocaine
• Most prominent action –
• Inactive orally due to high first pass metabolism
• Action of IV bolus lasts only 10-20 mins
1. Suppression of automaticity in ectopic foci
2. ↓ APD in Purkinje Fibres (PF) & ventricular muscles
Suppresses re-entrant ventricular arrhythmia either by
abolishing 1 way block or producing 2 way block
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• T1/2:
Early distribution phase – 8 mins
Later elimination phase – 2 hrs
• Dose:
50-100 mg iv bolus f/b 20-40 mg every 10-20 min
(Max 300 mg in 1 hr)
Or
1-3 mg/min infusion
• S/E: Dose related neurological effects
• No proarrhythmic potential & least cardiotoxic
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Mexiletine
• Local anaesthetic & orally active
• Automaticity in PF is ↓ by both ↓ phase 4 & ↑ threshold
voltage
• By ↓ rate of 0 phase depolarisation in ischemic PF, converts
1 way block into 2 way block
• Tremors – early sign of toxicity
Bradycardia, hypotension & accentuation of AV block – iv
• T1/2 – 9-12 hrs
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• Dose:
100-250 mg iv over 10 mins, 1mg/min infusion
Oral 150-200 mg TDS with meals
• Use:
Post MI ventricular arrhythmia as alternative to lidocaine
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Class IC
• High proarrhythmic potential when administered chronically
• Markedly ↓ rate of phase 0 depolarisation in Purkinje &
ventricular myocardial fibres
• ↓ automaticity, ↓ AV conduction & contractility
• Retard re-entry of retrograde & anterograde impulses
• Prominent depressant action on normal heart as well
Most potent Na+ channel blocker with more prominent
action on open state & longest recovery time (> 10 sec)
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Flecainide
• Prototype drug which markedly delays Na+ channel recovery
• No consistent effect on APD & no β blocking activity
• CAST study, ↑ mortality in patients recovering from MI
• Provokes arrhythmias during chronic therapy
Highest proarrhythmic potential
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Propafenone
• By blocking Na+ channels, depresses impulse
transmission & has profound effect on His-Purkinje as well
as accessory pathway conduction
• Anterograde & retrograde conduction in bypass tract
of WPW syndrome is retarded
• Prolongs APD & has β blocking property – can precipitate
CHF & bronchospasm
• Bioavailability & T1/2 differ considerably among individuals
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• Side effects:
Proarrhythmic events
• Dose:
150 mg BD – 300 mg TDS
• Use:
Prophylaxis & treatment of ventricular arrhythmias, re-
entrant tachycardia involving AV node / accessory
pathway & to maintain sinus rhythm in AF
↑ ventricular rate in atrial flutter by slowing atrial rate &
allowing 1:1 AV transmission
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Class II
• Slows sinus & AV nodal conduction which result in ↓ in
HR & prolongation in PR interval
• QT & QRS interval are not altered significantly
β blockers that competitively block catecholamine
induced stimulation of cardiac β receptors & depress
phase 4 depolarisation of pacemaker cells
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Propranolol
• Marked ↓ in slope of phase 4 depolarisation &
automaticity occur in SA node, PF & other ectopic foci
when same has ↑ under adrenergic influence
• ECG: Prolonged PR interval
• Dose:
Rapid action: Slow iv infusion 1-3 mg/min in 50 ml of
5% glucose solution (max 5 mg)
Oral: 40-80 mg TDS
For resistant ventricular arrhythmias - ~1000 mg
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• Uses:
Inappropriate sinus tachycardia
AES / VES, especially provoked by emotion or exercise
Prevent recurrences of PSVT
Recurrence of VT
Terminate torsades de pointes
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Esmolol
• Quick & short acting β1 blocker administered IV for
emergency control of ventricular rate in AF / AFL
• Terminate supraventricular tachycardia
• Sympathetically mediated arrhythmias seen in
pheochromocytoma & anaesthesia with halothane
• Dose:
Loading dose of 0.5 mg/kg in 1 min followed by 0.05–0.2
mg/kg/min i.v. infusion.
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Sotalol
• Prominent class III action of prolonging repolarisation by
blocking cardiac inward rectifier K+ channel
• Non-selective β blocker & effect is exhibited at doses
below than that required for prolongation of APD
Both Class II & III action
• Limitation: Prolongation of APD & QT, risk of dose
dependent torsade de pointes
• Dose: 80 mg BD orally
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Class III
• Mechanism of action:
• Prolong ERP
• QT & PR interval are prolonged
• Tissue remains refractory even after full repolarisation
Re-entrant arrhythmias are terminated
Prolongation of repolarisation by blocking outward
K+ channel during phase 3 of AP
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Amiodarone
• Iodine containing, highly lipophilic, long acting
• Conduction is slowed & ectopic automaticity is markedly
depressed, but that of SA node is only slightly affected
• Despite prolongation of APD, arrhythmia provoking
potential of amiodarone is low
Blocks Na+ channels
Mild β blocking activity
Ca2+ blocking action
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• Incompletely & slowly absorbed from GIT
On daily oral ingestion, action develops over several days
On IV injection, action develops rapidly
• Duration of action is exceptionally long; t1/2 – 3-8 weeks
• Side effects:
1. Pulmonary alveolitis & fibrosis – most serious
2. Hypotension, bradycardia & myocardial depression
– on IV injection & after drug accumulation
3. Corneal microdeposits
4. Photosensitisation & sun burn like pigmentation
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• Uses:
• Dose:
1. Resistant VT & recurrent VF
2. Maintain sinus rhythm in AF when other drugs have failed
3. Rapid termination of VT & VF and supraventricular
arrhythmia – IV injection
4. WPW tachyarrhythmia is terminated by suppression of
both normal & aberrant pathway
1. Orally 400–600 mg/day for few weeks, followed by
100–200 mg OD for maintenance therapy
2. Loading dose – 150 mg IV rapid infusion over 10
min f/b slow infusion of 1 mg/min for 6 hrs then
maintenance infusion of 0.5 mg/min for 24 hrs
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Dronedarone
• Amiodarone like drug without iodine atoms
• Shorter t1/2 – 1-2 days
• Dose:
400 mg BD orally
• Use:
Prevent recurrence in patients with persistent AF
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Bretylium
• Given only in ICU facility for treating refractory life-
threatening ventricular tachycardia & fibrillation
• Also known as Chemical / Pharmacological defibrillator
• Ventricular fibrillation: 5 mg/kg by rapid IV inj. &
repeated every 15-30 mins
• Side effects: Postural hypotension
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Dofetilide
• Pure Class III drug
• Prolongs APD & ERP by selectively blocking rapid
components of delayed rectifier K+ current
• Converts AF / AFL to sinus rhythm in ~30%; but more
effective in maintaining sinus rhythm in converted
patients
• Dose: 0.5 mg BD orally
16.02.2016

Vernakalant
• Mixed Na+ & K+ channel blocker
• Prolong atrial ERP & slows conduction through AV node
• Association & dissociation with Na+ channels is faster,
thus more effective in myocytes firing more rapidly
• Use:
Treatment of AF
• Dose:
IV infusion 3 mg/kg over 10 min then 2 mg/kg over 15 min
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Azimilide
• Blocks both slow & rapid components of K+ channels
• Low incidence of torsades de pointes
• Under trial to convert AF into sinus rhythm
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Tedisamil
• Upcoming Class III drug
• Given by IV infusion
• For conversion of AF & AFL to sinus rhythm
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Class IV
• Mechanism of action:
Blocks both activated & inactivated L-type Ca2+
channels in myocardium
↓ in rate of depolarisation (phase 4) in SA & AV
node
& slowed conduction through AV node
↑ in PR interval & ERP
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Verapamil
• Most prominent cardiac electrophysiological action
• Basic action is to depress Ca2+ mediated depolarization.
This suppresses automaticity and re-entry dependent on
slow channel response
• Most consistent action - prolongation of A-V nodal ERP
• Uses:
1. PSVT –
Terminate attack:- 5 mg IV over 2-3 min
Prevent recurrence:- 60-120 mg TDS orally
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2. To control ventricular rate in AF or AFL:
Dose dependent (40–120 mg TDS oral) reduction in
ventricular rate in AF and AFl, and is a first line drug
Injected i.v. for emergency control of ventricular rate in
AF and AFL (5-10 mg/hr IV infusion)
3. Re-entrant supraventricular and nodal arrhythmias
are susceptible to verapamil, but it is contraindicated in
broad QRS complex WPW tachycardia
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Diltiazem
• Alternative to verapamil – termination & prophylaxis of
PSVT
• For rapid control of ventricular rate in AF or AFL -
i.v. diltiazem is preferred over verapamil, because
• Dose: 5-15 mg/hr continuous infusion till adequate response
1. more easily titrated to the target heart rate
2. causes less hypotension or myocardial depression
3. used even in the presence of mild-to-moderate CHF
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Adenosine
Stimulates adenosine receptors (A1)
Opens G-protein coupled K+ channel & inhibits SA
nodal, atrial & AV nodal conduction
• Terminates re-entrant circuit through AV node & restores
normal sinus rhythm in PSVT
• Administered by rapid i.v. injection (over 1–3 sec) either
as the free base (6–12 mg) or as ATP (10–20 mg),
terminates within 30 sec. >90% episodes
of PSVT involving A-V node
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• very short t½ in blood (~10 sec)
• Advantages of adenosine for termination of PSVT are:
1. Efficacy equivalent to or better than verapamil.
2. Action lasts < 1 min; adverse effects are transient.
3. No haemodynamic deterioration; can be given to patients
with hypotension, CHF or on β blockers
4. Safe in wide QRS tachycardia
5. Effective in patients not responding to verapamil
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• Main side effects:
Facial flushing, shortness of breath, bronchospasm,
nausea, metallic taste
• Other uses of adenosine:
(a) Diagnosis of tachycardia dependent on A-V node
(b) To induce brief coronary vasodilatation during
certain
diagnostic/interventional procedures
(c) To produce controlled hypotension during surgery
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Atrial / Ventricular extrasystole
• Asymptomatic – no treatment required
• Symptomatic - β blocker
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Atrial fibrillation
• Definition:
Fast ectopic, irregular atrial activity (350-600 bpm)
• Ventricular rate ~ 100-150 bpm
• Treatment:
1. Underlying heart disease – find out cause
2. Rate control – 70-100 bpm
β blocker:- esmolol Acute therapy
CCB:- verapamil
Digoxin Chronic therapy
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3. Rhythm control:
Electrical
Acute therapy – DC shock
Chronic therapy – Amiodarone
Pharmacological
Acute therapy – Amiodarone
IV
Chronic therapy – Amiodarone
Propafenone
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Acute AF (> 48 hours)
Transesophageal echocardiography
Yes No
Don’t cardiovert immediately Immediate cardioversion
Warfarin for 3 weeks
Cardioversion
Warfarin for 4 weeks
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Chronic AF (>6 months)
a. Rate control with β blocker, CCB & Digoxin
b. ↓ Risk of ischemic stroke
Aspirin / Warfarin based on CHADS 2 score
If score ≥2 – warfarin
<2 – aspirin
16.02.2016

Atrial flutter
• Atrial rate 250-350 bpm
• Ventricular rate 75-175 bpm
• TOC – DC shock
• Recurrent atrial flutter:
A. Radiofrequency ablation (Elective procedure)
B. Digoxin
Atrial flutter Atrial fibrillation
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Wolf-Parkinson-White Syndrome
Tachycardia
• Termination:
Cardioversion, Radiofrequency ablation
• Maintenance:
1. Narrow QRS - Propafenone/procainamide
2. Wide QRS - Propafenone + verapamil / propranolol
or Amiodarone / sotalol
16.02.2016

PSVT
• An attack of PSVT can be terminated by reflex vagal
stimulation through
• Alternatively, or if it does not work, the drug of choice is
adenosine (i.v.). Other alternatives are i.v. injection of
verapamil / diltiazem / esmolol.
• Prevent recurrences - oral therapy with verapamil,
diltiazem or propranolol alone or combined with digoxin
TOC – Radiofrequency ablation
1. Valsalva maneuver,
2. Splashing ice cold water on face,
3. Hyperflexion (head between knees), etc.
16.02.2016

Ventricular tachycardia
• Definition:
≥ 4 consecutive ventricular extrasystole of > 100 bpm
• Unstable VT:
Immediate DC shock
Amiodarone (DOC) / Lidocaine / procainamide (IV)
• Prevention of recurrence / sudden cardiac death:
Best method – Intracardiac defibrillator
Alternative – Amiodarone / Propranolol / Propafenone
16.02.2016

Chronic ventricular tachycardia
• Nonsustained VT:
Suppression - Propranolol/amiodarone (oral)
• Sustained VT:
• Abolition - i.v. Amiodarone + propranolol
or cardioversion
or propafenone / lidocaine (i.v.)
• Maintenance therapy - Amiodarone/sotalol
(prevention of VF/arrest) Implantable defibrillator
16.02.2016

Ventricular fibrillation
• Grossly irregular, rapid & fractionated activation of
ventricles resulting in inco-ordinated contraction of
its fibres with loss of pumping action
• Termination:
Defibrillation + amiodarone (i.v.)
• Recurrence prevention:
Amiodarone (oral) / propranolol
16.02.2016

Bradyarrhythmias
• Results from failure of impulse generation within SA node
or
failure of impulse conduction through AV node
• Atrio-ventricular (A-V) block is due to depression of
impulse conduction through A-V node and bundle of His,
mostly due to vagal influence or ischaemia.
• First degree A-V block: Slowed conduction resulting in
prolonged P-R interval
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• Second degree A-V block: Some supraventricular
complexes are not conducted: drop beats
• Third degree A-V block: No supraventricular complexes
are conducted; ventricle generates its own impulse;
complete heart block
• Definitive treatment - pacing with cardiac pacemaker
• Drugs are of value only for acute/transient A-V block and
as an interim measure.
• Atropine: When A-V block is due to vagal overactivity, it
can be improved by atropine 0.6–1.2 mg i.m.
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• Sympathomimetics (isoprenaline): Overcome partial
heart block by facilitating A-V conduction and shortening
ERP of conducting tissues.
Also used in complete (3rd
degree) heart block to
maintain a sufficient idioventricular rate till external
pacemaker can be implanted
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Summary
• Abnormal automaticity or impaired conduction or both
underlies cardiac arrhythmia
• Anti-arrhythmic drugs used to prevent or treat irregularities
of cardiac rate & rhythm
• Anti-arrhythmic drugs themselves, may cause arrhythmias
by altering electrophysiological properties of cardiac fibres
• Asymptomatic atrial / ventricular extrasystole need not be
treated
• Ventricular arrhythmias are most important cause of
sudden cardiac death. Therefore, should be monitored
& treated in intensive coronary care unit
16.02.2016

References
• Goodman & Gilman’s The Pharmacological Basis of
Therapeutics 12th
Edition
• Longo, Fauci, Kasper, Hauser, Jameson and Loscalzo.
Harrisons’s Principles of Internal Medicine. 19th
Edition
• Rang & Dales’s Pharmacology 7th
Edition
• H. L. Sharma & K. K. Sharma’s Principles of Pharmacology 2nd
Edition
• Lippincott Illustrated Reviews: Pharmacology 6th
Edition

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