Transcript (5)ANTI-ARRHYTHMICS

Dr. Sanjib Das MD
VII. Antiarrhythmic Drugs
 A. Learning objectives
 What ionic and electrophysiological changes are associated
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with normal cardiac rhythm?
How might arrhythmias result from the effects of resting potentials on
action potentials? What factors may precipitate or exacerbate
arrhythmias?
Explain how disturbances either in impulse formation (by a latent
pacemaker or ectopic focus), or in impulse conduction (during
reentry or "circus movement") result in arrhythmias.
What are the major mechanisms of action of antiarrhythmic
drugs?
1. Sodium channel blockers (Class I)
Describe the [1] cardiac and extracardic effects, [2] toxic cardiac and
extra cardiac effects, [3] pharmacokinetics, and [4] therapeutic uses
for the following drugs:
(a) quinidine
(b) procainamide
(c) disopyramide
(d) lidocaine
How do tocainide and mexiletine differ from lidocaine?
How do flecainide, propafenone, and moricizine act, and what are
they used for?
 2. ß-Adrenergic blockers (Class II)
-What are the antiarrhythmic properties of propranolol and other
ß-adrenergic antagonists?
-How does esmolol differ from sotalol?
 3. Potassium channel blockers (Class III)
-What are the cardiac and extracardic effects of bretylium? How
is it administered and what is it used for?
-What is sotalol used for?
-Know that amiodarone also has Class I, II and IV actions
 4. Calcium channel blockers (Class IV)
-Describe the [1] cardiac and extracardic effects, [2] toxic
cardiac and extra cardiac effects, [3] pharmacokinetics, and [4]
therapeutic uses of verapamil.
 5. Miscellaneous
-What is the mechanism of antiarrhythmic action of adenosine
and what is it used for? What are its toxic effects?
-What are general principles of antiarrhythmic therapy?
-What guidelines can be used to decide whether arrhythmias
should be treated?
Cardiac impulse generation & conduction
 Normal pacemaker is the sinoatrial (SA) node which generates
60-100 impulses/min
 From the SA node, impulses spread through the atria to enter
the atrioventricular (AV) node where conduction slows to allow
time for atrial contraction to propel blood into the ventricles
 Finally, impulses spread over the His-Purkinje fibers to spread
to all parts of the ventricles
 SA node activity is regulated by reciprocal changes in:
• Sympathetic stimulation through b-adrenergic receptors
• Parasympathetic inhibition through muscarinic receptor
• b-adrenergic activation increases heart rate, contractility, and
ventricular pressure while muscarinic activation causes
opposite changes and decreases everything
Ionic Basis of Electrical Cardiac Impulses
 Transmembrane potential is determined by membrane concentrations
of, and permeability to: Na+, K+, and Ca2+
 K+ ion concentration being much higher inside the cell than outside,
promotes the outward movement of K+
 Conversely, Na+ ion concentration is much higher outside than inside
 Ion gradients are maintained by activity of Na+/K+ATPase
 At rest or during diastole, electrical charges are not flowing
•
The cell is negatively charged inside and positively charged
outside so that the sarcolemma is polarized
•
Sodium does not enter, despite the substantial concentration
gradient for Na+, because sodium channels are closed
•
K+ ions cross (because the sarcolemma is highly permeable to K+)
leaving unbalanced negative charges that make the cell negative
inside with a resting transmembrane potential of about -85 mV
Cardiac
Electrical
Activity
 Cardiac action potential has 5 phases
 Ionic changes in pacemaker cells during phase 4 cause spontaneous depolarization
 Latent pacemaker activity resides in the SA node, AV node, and Purkinje fibers which have a phase 4 slope
The steeper the phase 4 slope, the higher the automaticity which is highest in the SA node > AV node >
Purkinje cells
Differences in fast and slow response cell types
PNa
FAST
SLOW
PCa
+20
0
-20
PCa
-40
PK
-60
-80
PNa
Threshold potential
PCa
PK
PK
Slow
depolarization
Characteristics of Fast and Slow Response Cells in the
Myocardium
FAST RESPONSE
SLOW RESPONSE
Location: atria, ventricle, HisPurkinje
Located: SA and AV node
Rate of depolarization: fast
Rate of depolarization: slow
Conduction velocity: rapid
Conduction velocity: slow
Major ionic species involved in
depolarization: Na+
Major ionic species involved in
depolarization: Ca2+
Inhibitors of depolarization: Class I
antiarrhythmic agents (quinidine)
Inhibitors of depolarization: calciumentry blockers (verapamil, diltiazem)
Recovery of excitability: prompt;
ends with repolarization
Recovery of excitability: delayed;
outlasts repolarization
Catecholamines (SNS): little effect
on depolarization
Catecholamines: enhance
depolarization
Acetylcholine (PS): no effect on
depolarization
Acetylcholine: significantly
depresses depolarization
Cardiac Impulses & the ECG
 Electrocardiograms (ECG) record electrical changes occurring on the body
surface as action potentials spread over the heart
 P wave forms as depolarization spreads from the SA node through both atria
 At the AV node, conduction slows considerably to produce the interval
between P and Q waves (PR interval)
 Conduction through His-Purkinje fibers accelerates to produce the
• Small Q wave on reaching the septum
• QRS deflection spreading through the left ventricle
 Ventricular repolarization follows until the end of the T wave
 QRS duration = time required for ventricular activation
 QT interval = duration of ventricular action potential
 ECG recording is the most useful noninvasive method available for
diagnosing arrhythmia and evaluating effects of antiarrhythmic drugs
Cardiac Arrhythmias
 Are frequent clinical problems occurring in:
• 25% of patients treated with digoxin
• 50% of anesthetized patients
• 80% of patients with acute myocardial infarction
 May be initiated or worsened by:
• Ischemia, hypoxia, acidosis, or alkalosis
• Electrolyte abnormalities
• Autonomic imbalance due to catecholamine excess, scarred or
diseased myocardial tissues, drug toxicity (i.e., digoxin or
antiarrhythmic drugs)
 Classified according to anatomic origin as:
• Supraventricular – originating in the SA node, atria, or AV node
• Ventricular – originating in the ventricles
 Cause heart rates to become irregular, too fast, or too slow due to
abnormalities in:
• Site of impulse generation
• Impulse rate or regularity
• Impulse conduction
 Severity ranges from
 Mild & asymptomatic as in sinus bradycardia among athletes
 To hazardous & life-threatening as in ventricular fibrillation
Treatment of arrhthmias:
To terminate / prevent
Pharmacologic Method : with Anti Arrhyhthmic drugs.
Nonpharmacologic methods:
-Pacemakers
-Cardioversion
-Catheter ablation and
-Surgical methods .
Common Arrhythmias
A.Fibrillation
 Arrhythmias are often diagnosed based on
ECG appearance.
 Atrial premature beats appearing as
abnormal P waves are often asymptomatic.
A. Flutter
 Atrial flutter or fibrillation is common
in the elderly:
• Flutter - rates of >300 bpm often
occurring with AV block
• Fibrillation – atrial beating is
asynchronous and P waves are not
recognizable
 Ventricular premature beats (VPBs) are
discrete identifiable premature QRS
complexes
 Ventricular tachycardia is a run of at least
4 consecutive VPBs
 Ventricular fibrillation shown by
variations in size and frequency of ECG
deflections, is lethal if it lasts for more than a
few minutes
ECG Interpretation of Arrhythmia
 To be scheduled on a
 Optional Lecture can be
weekend?
delivered on request
 In 2-3 sessions
Case study-1
 ID: A 48 year old Nevisian male teacher Ex smoker not known to have
any medical illness presented to ER of Alexendra hospital with Hx of
palpitation for 7 hrs duration. He has no hx of chest pain, dyspnea,
orthopnea, PND, or syncopy , & no hx of hyperthyroidism
 O/E: pt was conscious & oriented. BP=115/75, HR=145/min irregular
irregular
CVS: normal S1+S2 , No murmur or L.L. edema
Chest: clear
Abdomen: soft & lax , with no organomegally
No thyromegally
 Investigations: MANAGEMENT TO BE DISCUSSED AT THE END
ECG: rapid AF
CX-ray: NAD
CBC: Hb:15, ESR:2, RBS: 108, CPK:81(normal)
Troponin o.o4 (normal)
PT: 11
FT3: 0.84 (N), FT4: 1.08(N)
RFT, LFT, S.lytes: all were normal
Case Study-2(m/c +ntation)
 A 56 years old man.
 Dx : Acute anterior wall MI
 ICU monitor multiple Ventricular Extrasystoles with
Ventricular Tachycadia
 Serum electrolytes : K = 2.7 “ 3.5 - 5 mmol/l”
Na = 136 “135-145 mmol/l”
Cl = 98 “ 98 - 106 mmol/l”
MANAGEMENT TO BE DISCUSSED AT THE END
Case Study- 3
Mr X is 67 years old Canadian male patient experienced dizziness &
SOB after walking to a nearby mal . He was brought to our ER for
further evaluation. No chest pain, palpitation or syncope. He is a
known case of diabetic type 2 since 10 months.
On examination: BP 160/95, pulse rate 125/min (regular irregular), RR
16.
Investigation:
Urinalysis : glucose > 1000
Cardiac enzyme within normal.
RFTs: sodium 129. LFTs: within normal
CBC: within normal RBS: 289 FBS: 178
Lipid profile: cholestrol 180 TG: 263
ECG: sinus rhythm with multiple multifocal premature ventricular
contraction.
Chest x-ray: cardiomegaly & congested lung
MANAGEMENT TO BE DISCUSSED AT THE END
Mechanisms of Arrhythmogenesis

Basic arrhythmogenic mechanisms generally result from:
• Disturbances in automaticity (impulse formation)
• Disturbances in impulse conduction
• Or combinations of both

Identifying the exact mechanism is clinically often difficult
 A.Disorders in automaticity or impulse formation
•
Automaticity is determined by the phase 4 slope which is :

Inhibited by vagal stimulation, ß-adrenergic blockade, or CCAs

Enhanced by ß-adrenergic stimulation, Ca2+, hypokalemia.
•
Arrhythmias from abnormal automaticity will occur whenever:

SA node rates are too fast or too slow, or

AV node and Purkinje cells overcome or usurp the SA node
•
Latent pacemakers can become ‘ectopic’ pacemakers by usurpation
Mechanisms of Arrhythmogenesis
 B. Disorders in impulse conduction
• Conduction can be prolonged by blocking impulses at any point along
the normal pathway
• Reentry or “circus movement” is a common conduction abnormality in
which a cardiac impulse reenters and excites the same pathway
repeatedly
• Three conditions required for reentry to occur:



Conduction has to be blocked by an anatomic or physiologic obstacle
creating a circuit around which the reentrant impulse can propagate
The block must be unidirectional at some point in the circuit such that
conduction is prevented in one direction but allowed to proceed in the
opposite direction
Conduction time around the circuit must exceed the effective
refractory period
Re-entry or Circus Movement:
(conduction abnormality in which a cardiac impulse reenters and
excites the same pathway repeatedly)
 Impulses are followed by a
refractory period during which the
tissue does not respond to
stimulation
 When impulses travel down two
branches they are extinguished at
the meeting point
 Unidirectional block prevents in one
direction but allows conduction to
proceed in the opposite direction
 As the impulse travels through the
intact branch upon reaching the
blocked site it is conducted in
retrograde fashion to initiate re-entry
DIFFERENT TYPES OF RE-ENTRY ARRHYTHMIAS
Abnormal Impulse Formation in Fast Response
Fibers
b. Afterdepolarizations:
These are depolarizations that
interrupt –
-Phase 3 (early afterdepolarizations,
EADs)
or
-phase 4 (delayed
afterdepolarizations, DADs).
DADs are triggered by abnormal
calcium influx→manifest as fast
heart rate and may be provoked by
digitalis glycosides, catecholamines,
and myocardial ischemia.
EADs are manifested as slow heart
rates and are responsible for
prolonged QT-interval related
arrhythmias.
Mechanisms of Antiarrhythmic Drug Action
 All Antiarrhythmic drugs work with ion channels with or without
involving ANS
 Antiarrhythmic drugs aim to:
• Reduce ectopic pacemaker activity by reducing the phase 4 slope
through blockade of sodium or calcium channels, and/or
• Modify conduction or refractoriness in reentrant circuits by slowing
conduction in reentrant arrhythmias
 Therapeutic doses usually affect abnormal tissues more (i.e., reduce
impulse generation more in ectopic pacemakers than in the SA node, or
slow conduction more in reentrant than in normal pathways)
 Toxic doses can affect even normal tissues (i.e., reduce impulse
generation in the SA node, or slow conduction in normal pathways) and
cause drug-induced arrhythmias like those occurring with digoxin
 Most antiarrhythmic drugs have a narrow margin of safety and adverse
effects can occur even with therapeutic doses
 Doses required to suppress the arrhythmia without producing adverse
effects have to be determined separately for each patient
Classification of Antiarrhythmic Drugs
 Class I = block Na+ channels elevate
threshold for excitation  inhibit automaticity
and conduction velocity  prolong PR and
QRS  prevent recurrence of reentrant
arrhythmias
 Many of these drugs also block K+ channels
 Further subdivided into:
• IA – lengthen APD & ERP; moderate Na+
channel block (Open or Activated) plus
K+ channel block
Quinidine (1) , procainamide (2),
disopyramide (13)
• IB – shorten APD; (mild Na+ channel
block )
Lidocaine (3), mexiletine (4) ,tocainide
• IC – minimal effect on APD; marked Na+
channel block
Flecainide (5) , propafenone, moricizine
NBME
 Class II = b-adrenergic blockade
 decreases in heart rate and
contractility
Propranolol (6) , timolol, and
other b-adrenergic
antagonists
 Class III = block K+ channels to
prolong APD and effective
refractory period
Amiodarone (7) , sotalol (8) ,
dofetilide, and ibutilide
 Class IV = CCAs like verapamil
(9) , diltiazem (10) , or bepridil
 Miscellaneous antiarrhythmics:
adenosine (11) , magnesium
(12) , potassium
NBME
NBME
 In a nutshell
To achieve clinical response by acting on
-Fast response fibre :use Class I & III
-Slow response(nodal tissues):Class II & IV
Class IA - QUINIDINE
 Admininistered as gluconate, sulfate, or polygalacturonate
salts
 Slows upstroke of the action potential, slows conduction, and
prolongs QRS duration, PR interval, and QT interval on
the ECG
 Used for maintaining sinus rhythm in atrial flutter or fibrillation
but must be with prior digitalization to nullify the proarrythmic
effect (next slide)
• Used much less today but still highly tested on certification
exams
 Two antiarrhythmic mechanisms:
NBME
• Mainly by blocking activated Na+ channels reduce
automaticity especially on ectopic pacemakers
• Also, blocks K+ channels to prolong APD and QT interval;
longer APD reduces reentry frequency and tachycardia
QUINIDINE – adverse effects
Quinidine produces many adverse effects:
 Blocks a-adrenergic receptors to cause vasodilation, marked
hypotension, and reflex tachycardia
 Blocks muscarinic receptors (relative sympathetic domination) - can
overcome its direct myocardial effects to result in faster atrioventricular
conduction; in patients with atrial fibrillation or flutter the vagal inhibition
can accelerate AV node conduction to increase ventricular rate and
cause paradoxical ventricular tachycardia- Arrhythmogenic/
NBME
Proaarrhythmic effect
 Gastrointestinal adverse effects consisting of diarrhea, nausea, vomiting
may cause cinchonism (headache, dizziness, tinnitus)
 Increases plasma digoxin (displaces from tissue binding sites) and
precipitate digoxin toxicity – A real situation often seen and to be
taken care off.
NBME
 Hyperkalemia increase chances of arrhythmia by prolonging
depolarization time (due to slow down of ungated potassium channel
activity)
NBME
 Syncope (recurrent lightheadedness and fainting) may occur due to
torsade de pointes
Torsade de pointes
NBME
 Atypical ventricular tachycardia manifested on the ECG by wide and narrow
(twisting of the points) QRS complexes
 Caused by changes in Na+or K+ channels  lengthens phase 2 of the action
potential  prolong QT interval and APD
 Occurs when the potassium channel gene (HERG) is blocked by antiarrhythmic
drugs (e.g., quinidine, sotalol) or electrolyte abnormalities (hypokalemia,
hypomagnesemia, hypocalcemia)
 Usually end spontaneously but can sometimes progress to ventricular
fibrillation  death
 In a nutshell
Any drug/condition that has strong antimuscuranic property or
directly blocks Potassium channel & prolong depolarization of
tissue can cause torsade de pointes
e.g-Few Antihistaminics
-All TCAs
-Quinidine
-Meperidine
-Sotalol
-Hypokalemia
-Hypomagnesemia
-Hypocalcemia
Class IA - PROCAINAMIDE
 A procaine analogue with electrophysiologic effects like those of quinidine, but has weaker
antimuscarinic activity 1.
 Ganglion-blocking activity may cause vasodilation and hypotension but these effects are
less pronounced than those of quinidine (because of no alpha blocking effect 2.)
 1+2 →less ANS induced A/E
 Most troublesome adverse effect with long-term therapy is a lupus-like syndrome with NBME
rash, arthralgia, arthritis, pericarditis, and renal lupus .(in slow acetylators)
 Other adverse effects include nausea and diarrhea (10%), rash, fever, hepatitis (> 5%), and
agranulocytosis (0.2 %) [immunological etiology]
 Eliminated by hepatic metabolism and renal excretion
 Short half-life of 3-4 hrs necessitates oral dosing with a sustained-release preparation
every 6 hours
 Better tolerated than quinidine when given IV, but not as useful for long-term oral treatment
due to its short half-life and adverse effects
 Procainamide does not elevate digoxin levels
 Given orally or parenterally for atrial and ventricular arrhythmias
Class IA Antiarrhythmics - DISOPYRAMIDE
 Cardiac effects very similar to, but more antimuscarinic than quinidine
or procainamide
 Intensity of antimuscarinic activity in descending order is:
• Disopyramide > quinidine > procainamide
 Antiarrhythmic profile and electrophysiologic effects resemble those of
quinidine and procainamide
 Approved for treatment of ventricular arrhythmias
 Not a first-line antiarrhythmic because its negative inotropic action may
induce CHF even without previous history of myocardial dysfunction
 Adverse effects caused by its pronounced anticholinergic activity
include:
• Urinary retention (usually in males with enlarged prostate)
• Dry mouth, blurred vision, constipation
• Worsening of preexisting glaucoma
Comparison of Class IA Antiarrhythmics
NBME
SIMILARITY
All block Na+ and K+ channels, and can induce torsade de pointes
DIFFERENCES
Quinidine
Antimuscarinic
actions
Procainamide Disopyramide
++
+
+++
Lupus-like
syndrome
-
++
-
 Plasma digoxin,
+
-
-
thrombocytopenia,
a-adrenergic block
Class IB Antiarrhythmics - LIDOCAINE
 Blocks both activated and inactivated sodium channels (mainly) in Purkinje
fibers and ventricular cells to:
• Elevate excitation threshold and reduce automaticity
• Suppress electrical activity of depolarized arrhythmogenic tissues
NBME
(ischemic or digitalized ) with minimal effects on polarized normal or atrial
tissues
In ischemic tissue, cells are partly depolarized because they lack the
amount of ATP needed to operate the Na+ pump. As a result, these cells
spend more time in the inactivated state than do cells in non-ischemic
tissue.
 ↓APD is due to blokade of slow Sodium window current (slow leakage of sodium
during 1,2 & 3 phase of AP) in ischemic fibres →THUS BRINGS APD BACK TO
NORMAL-Pseudo-arrhythmogenic (actually Antiarrhythmic) effect.
 Must be given intravenously: orally ineffective as only 3% appears in plasma
because of extensive first-pass hepatic metabolism
 Most effective against arrhythmias associated with depolarization as in
ischemia or digoxin toxicity but relatively ineffective against normally polarized
tissues as in atrial flutter or fibrillation ( Preferrential binding)
 Has no effect on normal impulse conduction as it does not affect K+ channels
Class IB Antiarrhythmics - LIDOCAINE
 Is the least cardiotoxic of currently used sodium blockers;
exacerbates ventricular arrhythmias in < 10% of patients
(good!!!) but, it may precipitate SA node standstill or worsen
impaired conduction in 1% of patients with myocardial infarction
 In patients with preexisting heart failure, large doses cause
hypotension by depressing myocardial contractility
 Most common adverse effects are neurologic: paresthesias,
NBME
tremor, nausea, lightheadedness, hearing disturbances, slurred
speech, and convulsions
 Seizures occur most commonly after rapid IV administration in
elderly patients
 Used mainly for acute termination of ventricular arrhythmias
post MI and to prevent ventricular fibrillation after
cardioversion & during open heart surgery.
NBME
Class IB Antiarrhythmics - MEXILETINE
 Lidocaine analog resistant to first-pass hepatic
metabolism and is effective orally
 Electrophysiologic and antiarrhythmic actions like those
of lidocaine
 Elimination half-life of 8-20 hrs allows oral administration
2-3 times daily
 Adverse effects of therapeutic doses are predominantly
neurologic including tremor, blurred vision, lethargy, and
nausea
 Useful for treatment of ventricular arrhythmias
 Also used for relief of chronic pain especially that due
to diabetic neuropathy and nerve injury
NBME
Class IC Antiarrhythmics
 All are given orally, but have been found to increase mortality from cardiac
arrest or arrhythmic sudden death in patients with recent myocardial infarction
 Practically blocks sodium channels of all states
NBME
 FLECAINIDE
• Blocks Na+ and K+ channels without antimuscarinic effects
• Used for maintaining sinus rhythm in supraventricular arrhythmias
• Very effective for suppressing premature ventricular contractions
• May exacerbate arrhythmias in patients with preexisting ventricular
tachyarrhythmias or myocardial infarction
 PROPAFENONE
• Blocks Na+ channels and structurally similar to propranolol with weak ßblocking activity
• Same uses as flecainide
• Has a metallic taste
• May exacerbate arrhythmias and cause constipation
 MORICIZINE
• Antiarrhythmic phenothiazine derivative for ventricular arrhythmias
• Potent sodium channel blocker that does not prolong APD
• May exacerbate arrhythmias; adverse effects are nausea and vomiting
Class II Antiarrhythmics:
ß-adrenergic blockers
NBME
 ↓Slope of Phase 4→↓SA & AV nodal activity
 Propranolol and metoprolol are most frequently used
for:
• Treatment of supraventricular and ventricular
arrhythmias caused by sympathetic stimulation
tachycardia
• To prevent ventricular fibrillation
 Esmolol is a short-acting drug used primarily for acute
arrhythmias occurring during surgery
 Beneficial effects are due to
 Diminished sympathetic activation of heart and blood
vessels 
 Reduced cardiac activity and reduced
vasoconstriction 

Hypotension and bradycardia 
 Diminished cardiac workload 
 Reduced myocardial oxygen demand
• Prevents recurrent infarction and sudden death in
patients with acute myocardial infarction
NBME
Harmful effects = negative inotropic effects may induce or worsen CHF in
patients with acute myocardial infarction or decompensated heart failure;
CNS penetration may cause insomnia and depression
Class III Antiarrhythmics: Amiodarone
 Given orally or IV for treatment of serious or life-threatening ventricular
arrhythmias
 Also effective for:
• Preventing recurrent ventricular arrhythmias
• Treatment of supraventricular arrhythmias like atrial fibrillation
• Adjuvant treatment to decrease uncomfortable discharges of implanted
cardioverter-defibrillators
 Decreases re-entry by blocking IKr+ (potassium rectifier current) to prolong
AP duration and QT interval (Class III activity)
 Also decreases rate of firing in pacemaker cells by blocking inactivated Na+ NBME
channels (Class I activity)
 Also blocks a- and b-adrenergic receptors and Ca2+ channels and thus
inhibit AV node conduction to produce bradycardia (Class II & IV activity)
 Relatively high efficacy with low incidence of torsade de pointes despite
prolonged QT
Amiodarone Pharmacokinetics
 Variably absorbed with 35-65% bioavailability
 Undergoes hepatic metabolism with the major metabolite,
desethylamiodarone, being bioactive
 Complex elimination half-life with rapid component of 3-10 days (50%
of the drug) followed by a slower component lasting for several
weeks.(overall t1/2 is 80days)→Loading dose required infront of such a
long 4-5 t1/2
 Measurable tissue levels occur even after a year.Long half life of
AmIodarone is +ce of Iodine which is not easily excreble out of the
body.
 Has many drug interactions as it is a substrate for hepatic
metabolism by CYP3A4:
• Tissue levels are increased by drugs that inhibit this enzyme (e.g., H2
NBME
NBME
NBME
blocker cimetidine)
• Tissue levels are decreased by drugs that induce this enzyme (e.g., anti-TB
rifampin)
• Inhibits other liver cytochome metabolizing enzymes to elevate levels of NBME
other drugs like digoxin or warfarin
Amiodarone Toxicity
 Because of its wide variety of actions, many adverse effects can result
including:
• Peripheral vasodilation especially with IV administration
• Asymptomatic bradycardia and AV block in patients with SA or AV node
disease
• Most important adverse effects are respiratory difficulties leading to fatal NBME
pulmonary fibrosis which occurs in 1% of patients. (inflammatory reaction
as a bodily defensive mechanism to remove iodine)[Other drugs cause
Pulmonary fibrosis and relavent PFTs are important ]
• Abnormal liver function and hepatitis (as a consequence of inflammatory
reaction against iodine)


Fatty change resembling alcoholic hepatitis
Liver fibrosis
• Skin reaction of Iodine with starches resulting in photodermatitis and
grayish-blue skin discoloration in sun-exposed areas (Smurf skin)
• Corneal microdeposits, reduced visual acuity, and optic neuritis progressing
to blindness
NBME
Amiodarone Toxicity
 Because of its wide variety of actions, many adverse
effects can result including:
• Neurologic effects as paresthesias, tremor, ataxia, and
headaches
• Thyroid dysfunction, both hypo- and hyperthyroidism
(iodine induced), caused by peripheral blockade of
converting T4 to T3.
• Gastrointestinal symptoms
 Has a long half-life and toxicity may persist long after it is
discontinued
 Because amiodarone can affect virtually every organ
system, treatment with it must be reevaluated whenever
new symptoms occur
NBME
Class III Antiarrhythmics: Sotalol
 Non-selective ß-adrenergic blocker that also prolongs APD and has
antiarrhythmic properties
 Formulated as a racemic mixture of d- and l-isomers
• All ß-adrenergic activity resides in the l-isomer
• AP prolongation is shared by both isomers
 May cause prolonged repolarization resulting in torsade de pointes
 Well absorbed orally with 100% bioavailability
 Half-life about 12 hours and excreted unchanged by kidneys
 6% incidence of torsade de pointes at highest daily dose
 Used for:
• Treatment of life-threatening ventricular arrhythmias
• Maintaining sinus rhythm in atrial fibrillation
• Treatment of supraventricular and ventricular arrhythmias in pediatrics
Class III Antiarrhythmics:
DOFETILIDE and IBUTILIDE
 Block the rapid component of the delayed rectifier potassium
current IKr to slow cardiac repolarization
 Ibutilide (IV only)
•
An intravenous Class III antiarrhythmic agent recommended for rapid
conversion of atrial fibrillation or atrial flutter to normal sinus rhythm.
 Dofetilide (orally)
 Used for the conversion and maintenance of normal sinus rhythm in
atrial fibrillation/flutter in highly symptomatic patients
 Common adverse effects are prolonged QT interval and
torsade de pointes
Class IV Antiarrhythmics: CCAs
 Bepridil, diltiazem, verapamil
 Orally active drugs that block L-type Ca2+ channels in myocardium and
vascular smooth muscles
 Nifedipine is not used as an antiarrhythmic as it is likely to cause reflex
tachycardia due to pronounced vasodilation
 By contrast, verapamil and diltiazem depress the SA and AV nodes directly
to:
• Decrease contractility
• Reduce SA node automaticity
• Slow AV node conduction
 Oral CCAs are used for:
• Acute and chronic management of PSVT
• Control of ventricular rate in atrial flutter or atrial fibrillation

Verapamil is more effective than digoxin
MISCELLANEOUS ANTIARRHYTHMICS
ADENOSINE
 Nucleoside normally formed by dephosphorylation of ATP then
metabolized by adenosine deaminase to form inosine
 Acts on two types of adenosine receptors:
A1 in myocardium  negative inotropic, chronotropic, and
dromotropic
• A2 in endothelium and vascular smooth muscles  coronary
vasodilation
•
NBME
 Enhances potassium conductance and inhibits Ca2+ influx 
prolonged AV node refractory period and slowed conduction
 Current drug of choice, by rapid intravenous injection, for converting
paroxysmal supraventricular tachycardia to sinus rhythm because
it is highly (90-95%) efficient with a very short action
NBME
 Adverse effects are flushing, shortness of breath or chest
burning, headache, hypotension, nausea, and paresthesia
NBME
MISCELLANEOUS ANTIARRHYTHMICS
MAGNESIUM
 Magnesium chloride or sulfate [parenteral]
 Mechanism of antiarrhythmic action unknown, but has been
used to prevent torsades de pointes and for digoxininduced arrhythmias
NBME
POTASSIUM
 Hypokalemia can produce ectopic pacemaker activity
especially during digoxin treatment
 Antiarrhythmic effect results by increasing K+ ions 
hyperpolarization lowered phase 4 slope  decreased
automaticity
NBME
Management of Atrial fibrillation

Consists of rate control and anticoagulation with warfarin (goal
INR of 2–3)
•
•
Rate control is defined as ventricular rate of 50–100 bpm with usual
daily activities and not exceeding 120 bpm except with moderate to
strenuous activity
Recommended treatments
NBME

Conventional rate control agents in young adults
(1) β-Blockers
(2) Calcium channel blockers
(3) Digoxin
•
Rate control agents in patients with heart failure, coronary artery
disease, or ongoing ischemia
Never calcium channel
(1) β-Blockers
blockers with heart failure
(2) Digoxin
•
Amiodarone or others agents are useful:
(1) When rate control with preferred agents fail
(2) When cardioversion is anticipated
GENERAL CHARACTERISTICS OF
ANTIARRHYTHMIC THERAPY
 Two types of benefits, both difficult to establish, are
reductions in:
[1] Arrhythmic symptoms like palpitations, syncope, or cardiac arrest
[2] Long-term mortality in asymptomatic patients
 All antiarrhythmic drugs have a narrow margin of safety
and the ratio between therapeutic versus toxic doses varies
widely from one patient to another; doses that are
therapeutically effective in some patients may be either
ineffective or toxic in others.
 The heart condition causing the arrhythmia strongly
influences the antiarrhythmic drug response; patients
with defective impulse conduction are greater risk for
developing complete AV block during treatment with quinidine
than those whose impulse conduction is normal.
GENERAL CHARACTERISTICS OF
ANTIARRHYTHMIC THERAPY
 Increased mortality from cardiac arrest or sudden death in patients
with recent myocardial infarction has occurred with almost all
antiarrhythmic drugs, and only ß-blockers have been shown to reduce
mortality.
 Initial treatment with any antiarrhythmic drug should first determine the
effective therapeutic dose for each patient, and then maintain that dose
for as long as necessary without producing adverse effects
 Some antiarrhythmic drugs have specific contraindications like:
• Prostatism for disopyramide (causes urinary retention due to marked
anticholinergic activity),
• Chronic arthritis for procainamide (causes lupus-like syndrome)
• Advanced lung disease for amiodarone (causes pulmonary fibrosis).
 Do not use digoxin, verapamil, or beta-blockers if atrial fibrillation is
associated with a known or suspected accessory pathway such as
Woolf-White-Parkinson (WPW) syndrome.
Extra Credit Quiz Section
Case study-1
 ID: A 48 year old Nevisian male teacher Ex smoker not known to have
any medical illness presented to ER of Alexendra hospital with Hx of
palpitation for 7 hrs duration. He has no hx of chest pain, dyspnea,
orthopnea, PND, or syncopy , & no hx of hyperthyroidism
 O/E: pt was conscious & oriented. BP=115/75, HR=145/min irregular
irregular
CVS: normal S1+S2 , No murmur or L.L. edema
Chest: clear
Abdomen: soft & lax , with no organomegally
No thyromegally
 Investigations: MANAGEMENT TO BE DISCUSSED AT THE END
ECG: rapid AF
CX-ray: NAD
CBC: Hb:15, ESR:2, RBS: 108, CPK:81(normal)
Troponin o.o4 (normal)
PT: 11
FT3: 0.84 (N), FT4: 1.08(N)
RFT, LFT, S.lytes: all were normal
Case Study-2(m/c +ntation)
 A 56 years old man.
 Dx : Acute anterior wall MI
 ICU monitor multiple Ventricular Extrasystoles with
Ventricular Tachycadia
 Serum electrolytes : K = 2.7 “ 3.5 - 5 mmol/l”
Na = 136 “135-145 mmol/l”
Cl = 98 “ 98 - 106 mmol/l”
MANAGEMENT TO BE DISCUSSED AT THE END
Case Study- 3
Mr X is 67 years old Canadian male patient experienced dizziness &
SOB after walking to a nearby mal . He was brought to our ER for
further evaluation. No chest pain, palpitation or syncope. He is a
known case of diabetic type 2 since 10 months.
On examination: BP 160/95, pulse rate 125/min (regular irregular), RR
16.
Investigation:
Urinalysis : glucose > 1000
Cardiac enzyme within normal.
RFTs: sodium 129. LFTs: within normal
CBC: within normal RBS: 289 FBS: 178
Lipid profile: cholestrol 180 TG: 263
ECG: sinus rhythm with multiple multifocal premature ventricular
contraction.
Chest x-ray: cardiomegaly & congested lung
MANAGEMENT TO BE DISCUSSED AT THE END
Treatment Objectives (in general)
 To control the heart rate
 To restore sinus rhythm
 To control ventricular rate
 To prevent or treat associated complications
 To treat the underlying condition e.g. thyrotoxicosis
 To prevent thromboembolism
Non Pharmacological T/t
– Reassure the patient
– Avoid excessive intake of alcohol, coffee or tea (if these are possible
precipitating factors)
– Massage of the carotid sinus on one side for a few seconds.
– This may terminate an attack of paroxysmal supraventricular
tachycardia.
– If the duration is less than 48 hours, patients may need immediate
– cardioversion
Pharmacological T/t
Atrial fibrillation
Digoxin, oral,250 micrograms 12 hourly over 24-48 hours,
Maintenance dose,250 micrograms daily
Alternative treatment or in combination with Digoxin
Atenolol, oral, (avoid in heart failure) 50-100 mg daily
Or
Bisoprolol, oral,1.25-10 mg daily
Antiplatelet and anticoagulant therapy
Aspirin, oral,75-300 mg daily
Or
Unfractionated Heparin, IV, 5,000-10,000 units
Or
Low molecular weight Heparin e.g. Enoxaparin, subcutaneously,
1 mg/kg daily (100 units/kg) every 12 hours, and then refer patients to a
specialist.
 Case 1: A 48 year old Nevician male teacher with Atrial
Fibrillation
 Management:
Patient initially admitted to the medical ward & started on Digoxin, but then it
was holded & transported to CC & started on Amiodarone IV infusion
(300mg IV over 1h then 1200mg over 24 hrs) & also he was started on IV
Heparin
The pt then converted to sinus rhythm after 24 hrs of starting Amiodarone
Pt then started on Amiodarone orally 200mg Tid
Next day he was transferred to medical ward on where he had sinus rhythm
continously there after.
He didn’t develop any AF since he was converted to Sinus Rhythm. Echo
was done & it was normal. He was discharged in a good & stable condition
with F/V appointment in cardiology OPD after 1 month
 Discharge medication:
1- ASA 81mg Po OD
2- amiodarone 200mg PO Tid X 5days
then
200mg PO OD X 1 month
NB: drug of choice for AF is Digoxin then Amiodarone
 Case 2: A 56 years old man diagnosed as Acute
anterior wall treated in the ICCU developed
multiple Ventricular Extrasystoles with Ventricular
Tachycadia
How would you manage this pt. ?
Case 3: Mr X is 67 years old Canadian male
diabetic patient developed Premature
Ventricular Complexes.
Treatment:
 Amiodarone 400 mg 2 tablets BID, then 1 tablet
TID, then 1 tablet BID, then 1 tablet OD.
 Glibendamide 2.5 mg PO BID for controlling DM.
Now answer following Qs before you practice MCQs
 What are the major mechanisms of action of antiarrhythmic
drugs?
 1. Sodium channel blockers (Class I)
 Describe the [1] cardiac and extracardic effects, [2] toxic cardiac and extra cardiac
effects, [3] pharmacokinetics, and [4] therapeutic uses for the following drugs:
 (a) quinidine
(b) procainamide
(c) disopyramide
(d) lidocaine
 How do tocainide and mexiletine differ from lidocaine?
 How do flecainide, propafenone, and moricizine act, and what are they used for?
 2. ß-Adrenergic blockers (Class II)
-What are the antiarrhythmic properties of propranolol and other ß-adrenergic
antagonists?
-How does esmolol differ from sotalol?
 3. Potassium channel blockers (Class III)
-What are the cardiac and extracardic effects of bretylium? How
is it administered and what is it used for?
-What is sotalol used for?
-Know that amiodarone also has Class I, II and IV actions
 4. Calcium channel blockers (Class IV)
-Describe the [1] cardiac and extracardic effects, [2] toxic
cardiac and extra cardiac effects, [3] pharmacokinetics, and [4]
therapeutic uses of verapamil.
 5. Miscellaneous
-What is the mechanism of antiarrhythmic action of adenosine
and what is it used for? What are its toxic effects?
-What are general principles of antiarrhythmic therapy?
-What guidelines can be used to decide whether arrhythmias
should be treated?
In a 55-year-old man who has an irregularly
irregular heart rate of 154 bpm and irregular QRS
complexes on the ECG, which of the following is
given intravenously but ineffective if given orally?
A) Moricizine
B) Quinidine
C) Lidocaine
D) Procainamide
E) Nifedipine
ANS = C
High first-pass effect
with lidocaine; metabolic
clearance
In a 45-year-old white man who has atrial flutter and
benign prostatic hyperplasia, which of the following
indicates the correct rank order of drugs most likely
to cause urinary retention when used for
antiarrhythmic therapy?
A) Disopyramide > procainamide > quinidine
B) Disopyramide > quinidine > procainamide
C) Procainamide > disopyramide > quinidine
D) Procainamide > quinidine > disopyramide
E) Quinidine > disopyramide > procainamide
Ans = B
Remember this order of
anticholinergic activity
Antiarrhythmic drugs
Sodium channel
blockers
(Class I)
β-adrenergic
blockers
(Class II)
Quinidine (Ia)
Procainamide (Ia)
Acebutolol
Esmolol
Metoprolol
Propranolol
Lidocaine (Ib)
Tocainide (Ib)
Mexiletine (Ib)
Potassium channel
blockers
(Class III)
Calcium channel
blockers
(Class IV)
Amiodarone
Sotalol
Dofetilide
Ibutilide
Verapamil
Diltiazem
Miscellaneous
Adenosine PSVT
Magnesium Toresade
Potassium
Digoxin toxicity
Ia = prolong duration of AP
Ib = reduces duration of AP
Ic = no change in AP duration
Ia & III = cause toresades de pointe
Which of the following would be most
preferred to treat a 57-year-old, who smokes
and has severe chronic obstructive
pulmonary disease, requiring Advanced
Cardiac Life Support for ventricular
fibrillation?
A. Adenosine
B. Amiodarone
C. Esmolol
D. Lidocaine
E. Quinidine
Answer: D
Normally amiodarone would
be considered drug of choice;
but not with lung disease
Which of the following is the drug of choice
to treat a 55-year-old asthmatic woman with
paroxysmal supraventricular tachycardia
(PSVT)?
A. Adenosine
B. Esmolol
C. Methoxamine
D. Procainamide
E. Sotalol
Answer: A
Adensosine drug of choice for
PSVTs