DRUG THERAPY FOR

ARRHYTHMIA
PREPARED BY: REYSAN S. COSAS, RPh
OBJECTIVES
1. Discuss the cardiac electrical conductivity pathway
2. Understand the cardiac action potential (both for
nonpacemaker and pacemaker cells)
3. Rationalize the electrocardiogram and its segments and
intervals
4. Define Arrhythmia
5. Describe the mechanisms of arrhythmia
6. Differentiate the types of arrhythmia
OBJECTIVES
7. Know the goals of antiarrhythmic drugs
8. Classify the antiarrhythmics based on their mechanisms of
action
9. Discuss the therapeutic uses and adverse effects of the
antiarrhythmics
10. Discuss the non-pharmacologic management of arrhythmia
 Cardiac Action Potential
(NONPACEMAKER CELL)

Divided into five phases (0,1,2,3,4)

 Cardiac Action Potential
(NONPACEMAKER CELL)

¢ PHASE 4 - resting phase

— Resting membrane potential
— Cardiac cells remain in until
stimulated
— Associated with diastole portion
of heart cycle
 Cardiac Action Potential
(NONPACEMAKER CELL)

¢ Addition of current into cardiac muscle (stimulation) causes:

¢ PHASE 0 = “upstroke + fast depolarization”

— Opening of fast Na channels and rapid depolarization
— Drives Na+ into cell (inward current), changing membrane potential
 Cardiac Action Potential
(NONPACEMAKER CELL)

¢ PHASE 1- “spike + a little bit repolarization”

— Closure of the fast Na+ channels
— K+ channels will open
— Phase 0 and 1 together correspond to the R and S waves of the ECG
 Cardiac Action Potential
(NONPACEMAKER CELL)

¢ PHASE 2 – “plateau”
— sustained by the balance between the inward movement of Ca+ and
outward movement of K +
— Has a long duration compared to other nerve and muscle tissue
— Corresponds to ST segment of the ECG.
 Cardiac Action Potential
(NONPACEMAKER CELL)

¢ PHASE 3 – “down slope + Fast repolarization”

— K+ channels remain open
— Allows K+ to build up outside the cell, causing the cell to repolarize
— Corresponds to T wave on the ECG
Cardiac Action Potential
(PACEMAKER CELL)
 ECG (EKG) Contraction
showing wave of ventricles

segments

Contraction Repolarization
of atria of ventricles
 PR INTERVAL
¢ Begins at the onset of the P wave and ends at the onset of the QRS
complex
¢ Represents the time the impulse takes to reach the ventricles from the
sinus node
¢ Normal values: 0.12 – 0.20 seconds
— Less than 0.12 seconds: short PR Interval (Ventricular Pre-excitation)
— Greater than 0.20 seconds: AV Block
 PR SEGMENT
¢ Begins at the endpoint of P wave and ends at the onset of the QRS
complex
¢ Represents the duration of the conduction from the AV Node down to
the Purkinje fibers
¢ Isoelectric (atrial systole and ventricular diastole)

¢ May deviate in the presence of atrial injury

 QRS COMPLEX
¢ Begins at the onset of the Q wave and ends at the endpoint of the S
wave
¢ Represents the duration of ventricular depolarization

¢ Duration prolongation may be due to:

— Aberrant conduction
— Ventricular ectopic or ventricular escape beats
— Ventricular hypertrophy
— Electrolyte imbalance
— Drug toxicity
 QT INTERVAL
¢ Begins at the onset of the QRS complex and ends at the endpoint of the
T wave
¢ Duration of ventricular depolarization and repolarization

¢ Duration of QT interval varies with heart rate, gender and age

— Short QT: Hypercalcemia, hyperkalemia, digitalis toxicity, class IB drugs
— Long QT: Slow heart rate, myocarditis, hypocalcemia, hypokalemia, CAD,
CHF, class IA and class III drugs
 ST SEGMENT
¢ Begins at the endpoint of S wave and ends at the onset of T wave
¢ Isoelectric (atrial diastole and ventricular systole)

¢ Depressed ST segment may be caused by myocardial ischemia

¢ Elevated ST segment occurs with recent cardiac injury, ventricular

aneurysms, pericarditis or Prinzmetal angina
ARRHYTHMIA
¢ Heart condition where disturbances/disorders in:
— Pacemaker impulse formation;
— Contraction impulse conduction; OR
— Combination of BOTH

Result in rate and/or timing of contraction of heart muscle

that is insufficient to maintain normal cardiac output
(CO).
Causes of arrhythmias
— Cardiac ischemia (MI)
— Atherosclerotic heart disease
— Excessive discharge or sensitivity to autonomic
transmitters
— Exposure to toxic substances
— Administration of general anesthetics
— Unknown etiology
 Mechanisms of Cardiac Arrhythmias

¢ Result
from disorders of impulse formation,
conduction, or both

¢ May result to heart rates that are either:

— Too slow (Bradycardia); or
— Too fast (Tachycardia).
DISORDERS OF IMPULSE FORMATION

¢ No signal from the pacemaker site (Bradyarrhythmias)

¢ Development of an ectopic pacemaker

— May arise from emergence of latent pacemakers
¢ Too slow firing at the SA node
¢ Abnormal acceleration of the latent pacemaker rate

— Automaticity – spontaneous depolarization (especially for

nonpacemaker cells)
AUTOMATICITY
¢ isthe ability of certain cells of the heart (nonpacemakers) to
undergo spontaneous depolarization, in which an action
potential is generated without any influence from nearby
cells
¢ Forms:
— Enhanced Automaticity – increase in the slope of phase 4
— Triggered Automaticity – second depolarization occurs
prematurely
¢ EADs
¢ DADs
 AFTERDEPOLARIZATIONS

¢ Occur during late ¢ Occur in late phase 3 or

phase 2 or phase 3 early phase 4
¢ Can lead to several ¢ Can lead to a series of
rapid action rapid depolarizations
potentials or a
prolonged series of
action potentials
AFTERDEPOLARIZATIONS
DISORDERS OF IMPULSE CONDUCTION
¢ May result in
— AV Block: Bradycardia (not involving reentry)
— Tachycardia (if reentrant circuit occurs – aka circus movement)

Reentrant
circuit
REENTRANT CIRCUIT (CIRCUS MOVEMENT)
 REENTRY
ARRHYTHMIA
 TYPES OF ARRHYTHMIA
¢ ARISING FROM THE SINUS NODE
— Sinus Tachycardia (100-150 bpm)
— Sinus Bradycardia (<60 bpm)
¢ ATRIAL ARRHYTHMIA
— Atrial Fibrillation (around 350 bpm)
— Atrial Flutter (250-350 bpm)
¢ NODAL AND OTHER SV ARRHYTHMIAS
— Atrioventricular Block (Prolongation of PR Interval)
 TYPES OF ARRHYTHMIA
¢ SUPRAVENTRICULAR TACHYCARDIA
— Intranodal SVT (Re-entry ‘circus’ Tachycardia)
— Extranodal SVT
¢ Wolff-Parkinson-White Syndrome
¢ Lown-Ganong-Levine Syndrome

¢ VENTRICULAR ARRHYTHMIAS
— Ventricular Ectopic Beats
¢ Abnormal QRS Complex
— Ventricular Tachycardia
¢ Rapid, wide QRS Complex
— Ventricular Fibrillation
¢ Chaotic; circulatory arrest occurs immediately
 OBJECTIVES OF ANTIARRHYTHMICS
¢ Restore the cardiac rhythm to normal
¢ Prevent arrhythmia recurrence

¢ Ameliorate the hemodynamic consequences of the

arrhythmia
¢ Reduce the risk of a more severe arrhythmia such
as ventricular fibrillation
GOALS OF ANTIARRHYTHMIC DRUGS
¢ Suppress automaticity – decrease the
frequency of discharge, an effect that is more
pronounced in cells with ectopic
pacemaker activity than in normal cells
— By decreasing the slope of phase 4 (diastolic) depolarization
— By raising the threshold of discharge to a less negative voltage
GOALS OF ANTIARRHYTHMIC DRUGS
¢ Prevent Re-entry
— by converting a unidirectional block into a
bidirectional block
¢Slow conduction

¢Increase the refractory period

MAJOR MECHANISMS
(1) Sodium channel blockade
(2) Blockade of sympathetic autonomic effects in the
heart
(3) Prolongation of the effective refractory period

(4) Calcium channel blockade

THERAPEUTIC OVERVIEW
¢ Na+ channel blockade
¢ β-adrenergic receptor blockade

¢ Prolong repolarization

¢ Ca2+ channel blockade

¢ Adenosine

¢ Digitalis glycosides
 CLASSES OF
ANTIARRHYTHMICS
¢ Class I (Na+ Channel blockers) ¢ Class II (β-blockers)
— Class Ia — Propranolol

¢ Quinidine — Atenolol
¢ Procainamide ¢ Class III (K+ channel blockers)
¢ Disopyramide — Amiodarone
— Class Ib — Bretylium
¢ Lidocaine — Ibutilide
¢ Tocainide — Sotalol
¢ Mexiletine ¢ Class IV (Ca2+ channel blockers)
¢ Phenytoin — Verapamil
— Class Ic ¢ Miscellaneous
¢ Flecainide — Adenosine
¢ Propafenone — Digitalis
¢ Moricizine
¢ Encainide
 Class I ANTIARRHYTHMICS
(FAST SODIUM CHANNEL BLOCKERS)

¢ Block the fast inward sodium current

¢ Are sometimes termed PVC killers

¢ Depress the rate of spontaneous phase 4

depolarization, or automaticity
¢Useful for abolishing premature ventricular contractions (PVCs)
¢ Depress Phase 0
SUBCLASS 1A
¢ Cause moderate Phase 0
depression
¢ Prolong repolarization (non-specific
blockade of potassium channels)
¢ Prolong the APD and dissociate
from the channel with intermediate
kinetics
¢ Increases ERP
Subclass 1a - QUINIDINE
¢ 1stantiarrhythmic used
¢ Slows the upstroke of the action potential and
conduction, and prolongs the QRS duration of the
ECG
¢ Treats both atrial and ventricular arrhythmias
(anticholinergic effects)
¢ Used for digitalis-induced arrhythmias
Subclass 1a - QUINIDINE
¢ Toxic effects:
— Excessive QT interval prolongation and induction of torsades de
pointes arrhythmia
— Diarrhea, nausea, and vomiting
— Cinchonism
— Idiosyncratic or immunologic reactions, including thrombocytopenia,
hepatitis, angioneurotic edema, and fever (rare)
 Torsades de pointes
is an uncommon and distinctive form of polymorphic
ventricular tachycardia (VT) characterized by a gradual
change in the amplitude and twisting of the QRS
complexes around the isoelectric line
Subclass 1a - PROCAINAMIDE
¢ Direct depressant actions on sinoatrial and atrioventricular
nodes
¢ Less anticholinergic effects than Quinidine
¢ Effective against most atrial and ventricular arrhythmias
¢ Drug of second or third choice for sustained ventricular
tachycardia associated with acute MI
Subclass 1a - PROCAINAMIDE
¢ Toxicities:
— QT interval prolongation, and induction of torsades de pointes
arrhythmia
— Syncope
— Syndrome of lupus erythematosus
— Nausea and diarrhea , rash, fever, hepatitis, and agranulocytosis
Subclass 1a - DISOPYRAMIDE
¢ Effectivein a variety of supraventricular arrhythmias
¢ Extended duration of action, used only for treating
ventricular arrhythmias
¢ Anticholinergic effects are even more marked than that of
quinidine
— Accounts for most adverse effects
SUBCLASS 1B
¢ Weak Phase 0 depression
¢ Shortened depolarization

¢ Decreased action potential

duration
Subclass 1b - LIDOCAINE
¢ Also acts as local anesthetic
— Blocks Na+ channels mostly in ventricular cells, also good for digitalis-
associated arrhythmias
¢ Not a depressant of AV node (shortened ERF)
¢ Agent of choice for ventricular tachycardia and prevention of
ventricular fibrillation (Given IV)
¢ Toxicities:
— Least cardiotoxic
— Neurologic - paresthesias, tremor, nausea of central origin, lightheadedness,
hearing disturbances, slurred speech, and convulsions
Subclass 1b – Other members
¢ MEXILETINE
— Oral lidocaine derivative, similar activity as Lidocaine
— Used in the treatment of ventricular arrhythmias

¢ PHENYTOIN
— Anticonvulsant that also works as antiarrhythmic similar to lidocaine
SUBCLASS 1C
¢ Strong Phase 0 depression
¢ No effect on action potential duration
Subclass 1c - FLECAINIDE
¢ A potent blocker of sodium and potassium channels
¢ Slows conduction in all parts of heart
¢ Very effective in suppressing premature ventricular contractions
¢ May cause severe exacerbation of arrhythmia even when normal doses
are administered
— patients with preexisting ventricular tachyarrhythmias
— with a previous myocardial infarction and ventricular ectopy
Subclass 1c - Other members
PROPAFENONE MORICIZINE
¢ Weak β – blocker ¢ A phenothiazine derivative
¢ Also some Ca2+ channel that was used for treatment of
blockade ventricular arrhythmias
¢ Spectrum of action is the ¢ Has been withdrawn from the
same with quinidine US market
¢ Used primarily for
supraventricular
arrhythmias
¢ Adverse effects
— metallic taste and constipation
— arrhythmia exacerbation
 SUMMARY OF
CLASS 1
ANTI-ARRHYTHMICS
 Class II ANTIARRHYTHMICS
(β–ADRENERGIC BLOCKERS)
¢ Basedon two major actions
1) Blockade of myocardial β–adrenergic receptors
2) Direct membrane-stabilizing effects related to Na+
channel blockade
 Class II
(β–ADRENERGIC BLOCKERS)

¢ PROPRANOLOL
— Causes both myocardial β–adrenergic blockade and
membrane-stabilizing effects
— Slows SA node and ectopic pacemaking
— Can block arrhythmias induced by exercise or
apprehension
 Class II
(β–ADRENERGIC BLOCKERS)
¢ Otherβ–adrenergic blockers have similar therapeutic effect as
propranolol

Metoprolol Nadolol Acebutolol

Pindolol Timolol Atenolol

Esmolol - short-acting; used in intraoperative and other acute

arrhythmias
 Class III
(K+ CHANNEL BLOCKERS)
¢ Prolong action potentials
¢ Developed because some patients are negatively sensitive to Na
channel blockers
¢ Cause delay in repolarization and prolonged refractory period*
*The time from phase 0 to the end of phase 3 of the action potential
 Class III ANTIARRHYTHMICS
(K+ CHANNEL BLOCKERS)
DRUG MECHANISM OF ACTION

Amiodarone Prolongs action potential by delaying

K+ efflux
Ibutilide Slows inward movement of Na+ in
addition to delaying K + efflux
Bretylium Has no effect on either automaticity or
conduction velocity
Blocks release of NE
Dofetilide Prolongs action potential by delaying
K+ efflux with no other effects
Class III – AMIODARONE
¢ Also blocks inactivated sodium channels
¢ Has weak adrenergic and calcium channel blocking actions
— Slowing of the heart rate and atrioventricular node conduction
¢ Has broad spectrum of actions
— High efficacy
— Low incidence of torsade de pointes

¢ Causes peripheral vasodilation (IV)

Class III – AMIODARONE
TOXICITIES OF AMIODARONE
¢ Bradycardia and heart block in patients with preexisting sinus or AV node
disease
¢ Fatal pulmonary fibrosis (1%)
¢ Hepatitis and abnormal liver function
¢ Skin deposits (photodermatitis)
¢ Corneal microdeposits
— halos on the peripheral visual fields
— Optic neuritis (rare)
¢ Hypothyroidism or hyperthyroidism
— Blocks the peripheral conversion of thyroxine (T4 ) to triiodothyronine (T3)
 Class III
(K+ CHANNEL BLOCKERS)
DRONEDARONE
¢ Similar effects as
amiodarone
¢ No thyroid or
pulmonary toxicity
BRETYLIUM
o First developed to treat
hypertension but found to
also suppress ventricular
fibrillation associated with
myocardial infarction
VERNAKALANT
¢ An investigational multi-channel
blocker that was developed for
the treatment of atrial fibrillation
¢ Adverse effects include;
— dysgeusia (disturbance of taste)
— Sneezing
— Paresthesia
— Cough
— hypotension
 Class III
(K+ CHANNEL BLOCKERS)
DOFETILIDE
¢ Approved for the maintenance
of normal sinus rhythm in
patients with atrial fibrillation
¢ Also effective in restoring
normal sinus rhythm in
patients with atrial fibrillation
IBUTILIDE
¢ Used for the acute conversion
of atrial flutter and atrial
fibrillation to normal sinus
rhythm
¢ Adverse effect is excessive QT
interval prolongation and
torsade de pointes
 Class IV ANTIARRHYTHMICS
(Ca2+ CHANNEL BLOCKERS)

¢ Slow rate of AV-conduction in patients with atrial fibrillation

— Verapamil
¢ blocks Na+ channels in addition to Ca2+
¢ also slows SA node in tachycardia

— Diltiazem
 Class V ANTIARRHYTHMICS
(Digoxin)

¢ Digoxin
— increases vagal activity via its central action on the central
nervous system, thus decreasing the conduction of electrical
impulses through the AV node and increases the refractory
period
 Class V ANTIARRHYTHMICS
(Digoxin)
TOXICITIES OF DIGOXIN
¢ May produce an increased automaticity characterized by
multifocal premature ventricular depolarizations
¢ Caution must be observed in digitalizing a patient who is
prone to atrial dysrrhythmias, because digitalis increases
atrial excitability and hence increases the risk of atrial
ectopy.
 MISCELLANEOUS
ANTIARRHYTHMIC
AGENTS
Adenosine
Magnesium
Potassium
MECHANISM OF ACTION
OF
ADENOSINE
ADENOSINE:
Effect on vascular smooth muscles
¢ In coronary vascular smooth muscle, adenosine binds to adenosine type
2A (A2A) receptors, which are coupled to the Gs-protein leading to an
increase in the cAMP
— stimulates KATP channels, which hyperpolarizes the smooth muscle, causing
relaxation
— causes smooth muscle relaxation by inhibiting myosin light chain kinase,
which leads to decreased myosin phosphorylation and a decrease in
contractile force
ADENOSINE:
Effect on vascular smooth muscles

¢ Adenosine also inhibits calcium entry into the cell through L-type
calcium channels
¢ In some types of blood vessels, adenosine produces vasodilation
through increase in cGMP
ADENOSINE:
Effect on cardiac tissues
¢ In cardiac tissue, adenosine binds to type 1 (A1) receptors, which are
coupled to Gi-proteins leading to decrease cAMP, causing inhibition of
L-type Ca+2 channels
— inhibits the pacemaker current - negative chronotropy
— decreases conduction velocity (negative dromotropic effect) particularly at
the AV nodes
ADENOSINE:
Effect on cardiac tissues
¢ On presynaptic purinergic receptors located on sympathetic nerve
terminals, adenosine inhibits the release of NE
— decreases heart rate and reduces conduction velocity, especially at the AV
node, which can produce atrioventricular block
 Inhibits adenylyl cyclase
reducing cAMP causing
hyperpolarization by
increasing outward K+ flux
through activation of
acetylcholine-sensitive K+
channels, especially in the
SA and AV nodes
 PHARMACOLOGICAL ACTIONS
AND USE OF ADENOSINE
¢ Increase in K+ conductance
— shortening of action potential duration
— hyperpolarization
— and decreased automaticity
¢ Drug of choice for prompt conversion of paroxysmal
supraventricular tachycardia to sinus rhythm
¢ Less effective in the presence of adenosine receptor blockers
(theophylline and caffeine)
¢ Effects are potentiated by adenosine uptake inhibitors
(dipyridamole)
 TOXICITIES OF ADENOSINE
¢ Flushing (in 20% of patients)
¢ Shortness of breath or chest burning in 10% of patients (due to
bronchospasm)
¢ Induction of high grade AV block (short-lived)

¢ Atrial fibrillation

¢ Less common toxicities include:

— Headache
— Hypotension
— Nausea
— Paresthesias
MAGNESIUM
¢ Indicated in digitalis – induced arrhythmias if hypomagnesemia is
present
¢ Also indicated in some patients with torsade de pointes
POTASSIUM
¢ Effects of increasing serum potassium
1. A resting potential depolarizing action
2. A membrane potential stabilizing action

¢ Hypokalemia
— Increased risk of early and delayed afterdepolarizations and ectopic
pacemaker activity especially in the presence of digitalis
¢ Hyperkalemia
— Depresses ectopic pacemakers and slows conduction
 NON PHARMACOLOGIC THERAPY
OF CARDIAC ARRHYTHMIAS

¢ RADIOFREQUENCY
CATHETER ABLATION
OR CRYOABLATION
(EXTREME COLD)
— The heat (RF ablation) or freezing
cold (cryoablation) destroy the
heart tissue causing the
fibrillation
 NON PHARMACOLOGIC THERAPY
OF CARDIAC ARRHYTHMIAS

¢ IMPLANTABLE
CARDIOVERTER
DEFIBRILLATOR (ICD)
— Automatically detects and treats
potentially fatal arrhythmias