AGENTS USED IN CARDIAC

ARRHYTHMIAS

MD2 LECTURE SERIES -

PHARAMACOLOGY

Dr. Ng’weina Francis Magitta, MD, PhD

University of Dar es Salaam
 Cardiac arrhythmias
Definition: a variation in either the site or rate of cardiac impulse
formation, and/or a variation in the sequence of cardiac impulse
propagation.
 Cardiac arrhythmias
• Frequent problem in clinical practice; occurring
in up to 25% of patients Rxted with digitalis,
50% of anaesthetized patients, and over 80% of
patients with MI.
• Some arrhythmias can precipitate more serious
or even lethal rhythm disturbances.
• Arrhythmias may require Rx because the
rhythm is too rapid, too slow, or asynchronous
can reduce cardiac output.
• Rx with antiarrhymic drugs can ppt lethal
arrhythmias in some patients.
 Rx of cardiac arrhythmias
• Arrhythmias can be treated with drugs
and with non-pharmacological therapies
such as pacemakers, cardioversion,
catheter ablation, and surgery.
Electrophysiology of Normal Cardiac Rhythm
Cardiac action potential
 Setting the membrane
potential
Nernst

[S ]
Eeq  61log i [S ]
Current Equil. Effect on Em
Pot.
o
INa +60 mV Depolarize

Goldman Hodgkin Katz IK -100 mV Repolarize

RT PK[K ]o  PNa[Na]o ICa +120 mV Depolarize

Em  ln
F PK[K ]i  PNa[Na]i
 Na+ K+

outside

-90 mV Ligand- Voltage-

Passive
gated gated

inside

Na+ K+
 How ion channels work

Closed Open Inactivated

Na+

Activation gate

Inactivation gate
 Na+ channels recycling through different
conformational states during the cardiac action
potential.
 Ionic Basis of the Action
Potential

Ackerman and Clapham. 1999. In Mol. Basis of Cardiovascular Disease. Ed. Chien. 284.
Action potential
 The fast cardiac action potential

Ca 2+
Ca 2+
+55 mV 1
2 K+
+ 3 K+
Na

0 Na+

4 4

-90 mV K+
Na/K ATPase
 Effect of local anesthetics on the fast cardiac action potential

Refractory Period
Na +

Slope phase 0 = conduction velocity Longer RP due to slower recovery

from inactivation

Increased threshold
 Effect of drugs that block K channels

1 Refractory Period
2 K +

3 K+

0
4 4

Increase action potential duration (APD)

 Slow cardiac action potential

Ca2+
2
Ca2+ K+
3
0

If 4
4

Na, K
 Effect of Ca 2+ channel blockers

2 Refractory Period
Ca2+
3
0

4
4

Slope of phase 0 = Conduction velocity

 Drugs affecting automaticity

3
0

4
4
β agonist

Muscarinic agonists, Adenosine

Phases of ventricular action potential
 Ion permeability changes and transport
processes that occur during an action potential
Cardiac action potential
Cardiac action potential
Cardiac action potential
ECG
Current drugs work by
blocking channels
Na+

Na+
Effects of Na+ channel blockade
 Conduction velocity (CV)
- main effect
 AP threshold =
QT QT automaticity = pacing and
defibrillation thresholds.
EKG  Slight decrease in action
potential duration
 Negative inotropy - Lower
Na+ permeability through
the channel means less
AP Na+ in the cell. Less
Na+ in the cell means
more driving force for the
Na/Ca exchanger. More
Na/Ca exchange means
less intracellular Ca2+ and
less contractility.
 Effects of K+ channel block

QT QT  Action potential
duration (APD) =
EKG refractoriness - main
effect
 Positive inotropy -
The longer the action
AP potential is the more
Ca2+ enters the cell.
Unfortunately, this
effect generally is not
seen clinically.
Ca2+ channel effects
 Inhibit the SA node, AV
node, and some tissue
with abnormal
automaticity dependent on
Ca2+ channels (e.g. right
ventricular outflow
tachycardia) - main effect
 Generally little effect on
the APD
 Stops triggered activity -
EADs depend on Ca2+
channels to open to
depolarize the cell.
DADs result from
Ca2+ overload of the cell.
In either case, Ca2+
channel blockers
improve the situation.
 Mechanisms of arrhythmia
 Automaticity
 Normal (e.g. sinus tachycardia)
 Abnormal (e.g. reperfusion arrhythmias)
 Triggered activity
 Early afterdepolarizations associated with QT prolongation
(torsades de pointes)
 Delayed afterdepolarizations associated with Ca2+ overload
(e.g. digoxin)
 Reentry
 Fixed obstruction (e.g. atrial flutter)
 Leading circle (e.g. ventricular fibrillation)
Enhanced automaticity & Triggered
Re-entry
 Re-entry

Wolf-Parkinson-White Syndrome (WPW)

CLASS ACTION DRUGS

I A. Moderate phase 0 Quinidine, procainamide

I B. No change in phase 0 Lidocaine
I C. Marked phase 0 Flecainide

II Beta-adrenergic blockers Propranolol, esmolol

III Prolong repolarization Amiodarone, Sotolol

Dofetalide, ibutilide

IV Calcium channel blockers Verapamil, diltiazem

 VAUGHAN WILLIAMS CLASSIFICATION OF
ANTIARRHYTHMIC DRUGS

 Class I – Na+ channel blockers

 Class Ia - Decrease conduction velocity and increase APD.
Used most frequently for conversion of atrial
flutter/fibrillation and maintenance of sinus rhythm.
 Class Ib - Minimal change in conduction velocity and a
slight decrease in action potential duration. Not useful for
atrial arrhythmias. Used for ventricular arrhythmias,
especially those associated with myocardial
infarction/ischemia but not for prophylaxis.
 Class Ic - Marked prolongation of CV. Used for atrial
flutter/fibrillation in patients with structurally normal hearts.
 Vaughan Williams
classification
 Class II - β blockers
 Class III -Prolong APD - used in atrial and ventricular
arrhythmias
 Class IV – Ca2+ channel blockers. Dihydropyridines are
not effective antiarrhythmic drugs because they have little
effect on cardiac Ca2+ channels.
 Miscellaneous
 Adenosine
Potentiated by dipyridamole, an adenosine uptake
inhibitor
Inhibited by methylxanthines (e.g. caffeine) which
block the receptor
Use with care in cardiac transplant recipients
because of hypersensitivity.
 Class 1A agents: Procainamide,
quinidine, disopyramide
Absorption and elimination (oral or iv)
Effects on cardiac activity
Intermediate binding offset kinetics

 conduction ( phase 0 of the action potential (Na+))

 refractory period ( APD (K+) and  Na inactivation)

 automoticity ( slope of phase 4, fast potentials)

 increase threshold (Na+)

Quinidine has anticholinergic (atropine like action) to speed AV

conduction used with digitalis, β blocker or Ca channel blocker
Quinidine is also an alpha receptor antagonist

Effects on ECG  QRS,  PR, QT

Class 1A (cont.)
Uses
Wide spectrum:

Quinidine : maintain sinus rhythms in atrial fibrillation and flutter

and to prevent recurrent tachycardia and fibrillation

Procainamide: acute treatment of supraventricular and ventricular

arrhythmias

Side effects
Hypotension, reduced cardiac output
Proarrhythmia (generation of a new arrhythmia) eg.
Torsades de Points (QT interval)
Dizziness, confusion, insomnia, seizure (high dose)
Gastrointestinal effects (common)
Lupus-like syndrome (esp. procainamide)
 Quinidine – class Ia
 Diastereomer of quinine from the
cinchona plant
 α Adrenergic block and vagolytic -
results in hypotension when given IV
H and acceleration in AV conduction if
used alone.
H
 Hepatic metabolism
HO
N
 Inhibits CYP450 2D6 and raises
H
digoxin levels
O  Side effects
 diarrhea (25-50%)

N  reversible thrombocytopenia
 cinchonism (headache and
Quinaglute, Quinidex tinnitus)
 hepatitis
 bone marrow suppression
 lupus-like syndrome
 Procainamide – class Ia
 Metabolite, N-acetyl
procainamide (NAPA),
blocks K+ channels
 Marked variations in
metabolism based on
N acetylation rates
HN  Better tolerated IV than
H2N
quinidine
O
 May cause lupus-like
syndrome when given
Procanbid, Pronestyl long term (30%).
Most (70%) get
antinuclear antibodies,
especially slow
acetylators.
 Renal excretion
 Disopyramide - Ia
 Rarely used except
for hypertrophic
cardiomyopathy and
N
neurocardiogenic
H2N syncope
 Prominent
O anticholinergic effects
N
 Significantly
negatively inotropic

Norpace
Class 1B agents: Lidocaine, mexiletine,
phenytoin
Absorption and elimination
Lidocaine: iv only
Tocainide and mexiletine: oral

Effects on cardiac activity

Fast binding offset kinetics

No change in phase 0 in normal tissue (no tonic block)

APD slightly decreased (normal tissue)

 increase threshold (Na+)

 phase 0 conduction in fast beating or ischemic tissue,

Effects on ECG
None in normal, in fast beating or ischemic  QRS
Class 1B (cont.)
Uses
acute : Ventricular tachycardia and fibrillation (esp. during
ischemia)

Not used in atrial arrhythmias or AV junctional arrhythmias

Side effects
Less proarrhythmic than Class 1A (less QT effect)
CNS effects: dizziness, drowsiness
Lidocaine – class Ib

 Given IV because of
hepatic first pass
metabolism
NH N
 Toxicity is
neurological such as
O tremor, nystagmus, or
delirium
Other class Ib drugs

 Mexiletine
 Equivalent to oral lidocaine
 Hepatic metabolism
 GI symptoms; take with food
 Phenytoin (Dilantin)
 Not frequently used
 Liver metabolized
 Tocainide (Tonocard) - not frequently used
because of potential bone marrow suppression
and pulmonary fibrosis
 Class 1C agents: Flecainide and
propafenone
Absorption and elimination
oral or iv

Effects on cardiac activity

very slow binding offset kinetics (>10 s)

Substantially   phase 0 (Na+) in normal

 automoticity ( threshold)

 APD (K+) and  refractory period, esp in

rapidly depolarizing atrial tissue.

Effects on ECG

 PR, QRS, QT

 Class 1C (cont.)
Uses
Wide spectrum

Used for supraventricular arrhythmias (fibrillation and

flutter)

Premature ventricular contractions (caused problems)

Wolff-Parkenson-White syndrome

Side effects
Proarrhythmia and sudden death especially with chronic
use (CAST study)
increase ventricular response to supraventricular
arrhythmias
CNS and gastrointestinal effects like other local anesthetics
Class Ic  Flecainide (Tambocor)
 increased mortality after MI in
CAST
 has minor K+ channel blocking
properties
 common side effect is blurred
vision
HN
 Propafenone (Rythmol)
 S-(+) enantiomer is a β blocker

 metabolized by CYP450 2D6 - 5-

NH
F F
hydroxy propafenone blocks Na+
O channels but not β receptors
F O
 increases digoxin (83%),
F warfarin, metoprolol
O
 Renal and liver dose
F F adjustments
 Moricizine
 phenothiazine derivative

 increased mortality after MI in

CAST-II
 CLASS II AGENTS: PROPRANOLOL,
ACEBUTOLOL AND ESMOLOL

Absorption and elimination

Propranolol: oral, iv

Esmolol: iv only (very short acting T½, 9 min)

Cardiac effects
 APD and refractory period in AV node to slow AV
conduction velocity

 decrease phase 4 depolarization (catecholamine

dependent)

Effects on ECG
 PR,  HR
Class II (cont.)
Uses
treating sinus and catecholamine dependent tachy
arrhythmias

converting reentrant arrhythmias in AV

protecting the ventricles from high atrial rates (slow AV

conduction)

Side effects
bronchospasm
hypotension
don’t use in partial AV block or ventricular failure
 CLASS III AGENTS: AMIODARONE,
SOTALOL, IBUTILIDE, DOFETILIDE
Amiodarone
Absorption and elimination
oral or iv (T 1/2 about 3 months)

Cardiac effects
 increase refractory period and  APD (K+)
 phase 0 and conduction (Na+)
 threshold
 phase 4 (β block and Ca++ block)
 speed of AV conduction

Effects on ECG
 PR, QRS,  QT,  HR
Class III (cont.)

Amiodarone (cont.)
Uses
Very wide spectrum: effective for most arrhythmias

Side effects: many serious that increase with time

Pulmonary fibrosis
Hepatic injury
Increase LDL cholesterol
Thyroid disease
Photosensitivity

May need to reduce the dose of digoxin and class 1 antiarrhythmics

 Amiodarone – class III
 Most effective drug for maintenance of sinus rhythm
in patients with atrial fibrillation and for decreasing
risk of ventricular tachyarrythmias
 Has little effect on contractility and is one of the best
drugs to use in heart failure
 Shown to improve mortality in nonischemic
cardiomyopathy patients at risk of sudden death,
I
possible advantageous after MI
O
O
N
 Has properties of all four classes (i.e. Na+, K+, Ca2+
channel blocker and noncompetitive ,β blocker)
I
 Can be given IV or oral
O
 Lipophilic - requires a loading dose and has a half
life of weeks (800-1600 mg/day for 1-3 weeks, 600-
800 mg for 1 month)
 Can be used in renal failure
 Onset of action 2 days – 2 weeks even with loading
 CAMIAT (arrhythmia) , EMIAT (EF<40%) showed
safety in structural heart disease
 Get baseline CXR, PFTs, LFTs, TFTs
Amiodarone side effects
 A thyroxine analog containing iodine that
can give hypothyroid or hyperthyroid
symptoms
 Nausea
 Pulmonary fibrosis that can be irreversible
and life threatening - unusual at doses
used for atrial fibrillation (200 mg/day)
 gallium scan and DLCO reduction of
30% are helpful
 10% fatal, most reversible

 Hepatitis
 Corneal deposits - usually clinically
unimportant and reversible
 Myopathy
 Skin deposit that leads to photosensitivity
and bluish tint
 Neuropathy
 Raise levels of digoxin (50-75%), warfarin
(50-100%), diltiazem, cyclosporin

N Engl J Med 1997; 337:1814

Class III (cont.)
Sotolol
Absorption oral

Cardiac effects
 APD and refractory period in atrial and ventricular tissue

Slow phase 4 (β blocker)

Slow AV conduction

ECG effects  QT,  HR

Uses
Wide spectrum: supraventricular and ventricular tachycardia

Side effects
Proarrhythmia, fatigue, insomnia
Class III (cont.)
Ibutilide
Absorption
rapid iv infusion

Cardiac effects
pure Ikr channel blocker

also activates inward Na+ current

net result in  APD

ECG effects QT

Uses
conversion of atrial fibrillation and flutter

Side effects
Torsades de pointes
Class III (cont.)
Dofetilide
Absorption oral

Cardiac effects
pure Ikr channel blocker

 APD and refractory period

ECG effects  QT

Uses
maintain sinus rhythm in pts with atrial fibrillation

Side effects
restricted use
Torsades de pointes
 Other class III agents
 d,l – Sotalol (Betapace)
 l-Enantiomer is a non selective β blocker and K+ channel blocker;
d-enantiomer is a pure K+ channel blocker
 d-Sotatol increased mortality in the SWORD trial
 Renal dose adjustments required
 Do not start if QTc >450 ms, stop if QTc >520 ms
 Bretylium
 Generally used in ACLS protocols only

 Causes degranulation of sympathetic neurons

and prevents reuptake
 Causes orthostasis, nausea
 Ibutilide (Covert)
 Used IV for acute conversion of atrial flutter/fibrillation
 About 40% effective (atrial flutter > atrial fibrillation) with about
<10% incidence of torsades (>in low EF)
 Activates a prolonged Na+ current
 Similar structurally to sotalol
 t½ = 6-9 hours, liver metabolism
Other class III agents (cont.)
 Dofetilide (Tikosyn)
 Renal excretion

 DIAMOND CHF and MI showed safety in structural

heart disease
 Avoid verapamil, cimetidine, trimethoprim,
prochloperazine, megestrol, or ketoconazole, which
alter renal excretion
 Do not start if QTc >440 ms, stop if QTc >500 ms

 Azimilide
 Not approved yet
 Blocks a new class of K+ channels

 Probably safe in low EF structural heart disease

 Being developed for atrial arrhythmias

 No renal dose adjustments necessary

 CLASS IV AGENTS: VERAPAMIL AND
DILTIAZEM

Administration
verapamil: oral or i.v.
diltiazem: oral

Cardiac effects
slow conduction through AV (Ca++)

 refractory period in AV node

 slope of phase 4 in SA to slow HR

Effects on ECG
 PR,  HR (depending of blood pressure
response and baroreflex)
Class IV (cont.)

Uses
control ventricles during supraventricular tachycardia

convert supraventricular tachycardia (re-entry around AV)

Side effects
Caution when partial AV block is present. Can get asystole
if β blocker is on board
Caution when hypotension, decreased CO or sick sinus
Some gastrointestinal problems
 ADDITIONAL ANTIARRHYTHMIC AGENTS

Adenosine
Adminsitration
rapid i.v. bolus, very short T1/2 (seconds)

Mechanism
natural nucleoside that binds A1 receptors and activates K+
currents in AV and SA node –  APD, hyperplarization → HR

 Ca++ currents -  refractory period in AV node

Cardiac effects
Slows AV conduction

Uses
convert re-entrant supraventricular arrhythmias
hypotension during surgery, diagnosis of CAD
Digioxin (cardiac glycosides)
Mechanism
enhances vagal activity ( K+ currents,  Ca++ currents, 
refractory period
slows AV conduction and slows HR
Uses
treatment of atrial fibrillation and flutter

Atropine
Mechanism
selective muscarinic antagonist
Cardiac effects
block vagal activity to speed AV conduction and increase HR
Uses
treat vagal bradycardia

Magnesium
treatment for tachycardia resulting from long QT
 Proarrhythmia

 Class I proarrhythmia may be drug induced

Brugada syndrome
 Class III proarrhythmia is related to QT
prolongation
 Pearls
 Drugs work best when the EF is high.
 Drugs have most proarrhythmia when EF is low.
 Use amiodarone, quinidine, mexiletine, moricizine,
ibutilide, or lidocaine in renal failure.
 Amiodarone’s risk of torsades is poorly related to QT
prolongation.
 Classes Ia, Ic, II, IV are negatively inotropic.
 Only amiodarone, sotalol, and dofetilide are known safe
in low EF patients.
 Use AV blockers with class Ic drugs for PAF.
 Start everything but amiodarone in house.
 Monitor QRS duration with class Ic drugs.
 DRUGS, ABLATION, OR
DEVICES?
 Common drug uses
 Supraventricular rhythms not curable by other means, such as
atrial fibrillation. Since atrial fibrillation is present in up to 10% of
the elderly population, this is the major use of antiarrhythmic drugs.
 Termination of hemodynamically stable rhythms including VT or
SVT.
 Treatment of hemodynamically stable rhythms, especially if they
occur frequently. For example, treating a hemodynamically stable
but incessant VT with an ICD would result in multiple shocks and
rapid depletion of the ICD battery.
 Combination therapy with ICDs to decrease the shock
occurrences.
 When other methods are impossible to use. For example, the
patient is a poor candidate for ablation or an ICD because of
infection, coagulopathy, etc.
 DC Cardioversion (electric shock)

Treatment of choice for unstable, life-threatening

cardiac arrhyghmias.
Ablation therapy
Mechanical devices
Implantable defibrillator: for sudden death has been shown to be more
effective than pharmacological therapy for increasing longevity
END!