Antiarrhythmic Drugs
Ira R. Friedlander, M.D.
Background
To function efficiently, heart needs to contract
sequentially (atria, then ventricles) and in synchronicity.
Relaxation must occur between contractions (not true for
other types of muscle [tetany  contract and hold
contraction for a length of time])
Coordination of heartbeat is a result of a complex,
coordinated sequence of changes in membrane
potentials and electrical discharges in various heart
tissues
Arrhythmia
Heart condition where disturbances in



Pacemaker impulse formation
Contraction impulse conduction
Combination of the two
Results in rate and/or timing of contraction of
heart muscle that is insufficient to maintain
normal cardiac output (CO)
To understand how antiarrhythmic drugs work,
you need to understand the electrophysiology
of normal contraction of heart
Normal heartbeat and atrial arrhythmia
Normal rhythm
Atrial arrhythmia
AV septum
Ventricular Arrhythmia
Ventricular arrhythmias are
common in most people and are
usually not a problem but…
VA’s are most common cause of
sudden death
Majority of sudden death occurs in
people with either a previously
known heart disease or history of
VA’s
Medications which decrease
incidence of VA’s do not
decrease (and may increase) the
risk of sudden death treatment
may be worse then the disease!
Electrophysiology - resting potential
A transmembrane electrical gradient (potential) is
maintained, with the interior of the cell negative with
respect to outside the cell
Caused by unequal distribution of ions inside vs. outside
cell



Na+ higher outside than inside cell
Ca+ much higher outside than inside the cell
K+ higher inside cell than outside
Maintenance by ion selective channels, active pumps
and exchangers
ECG (EKG) showing wave
segments
Contraction
of atria
Contraction of
ventricles
Repolarization of
ventricles
Excitable tissues in heart
Slow response tissues (mainly Ca
channels)
SA node
AV node
Fast response tissues (mainly Na
channels)
atrium
ventricle
bundle of His
Purkinje fibers
Cardiac Action Potential
Divided into five phases (0,1,2,3,4)

Phase 4 - resting phase (resting membrane potential)
Phase cardiac cells remain in until stimulated
Associated with diastole portion of cardiac cycle
Addition of current into cardiac muscle (stimulation)
causes

Phase 0 – opening of fast Na channels and rapid depolarization
Drives Na+ into cell (inward current), changing membrane potential
Transient outward current due to movement of Cl- and K+

Phase 1 – initial rapid repolarization
Closure of the fast Na+ channels
Phase 0 and 1 together correspond to the R and S waves of the
ECG
Cardiac Na+ channels
Early
+30 mV
repolarization
Inactivated
1
Plateau
phase
2
0 mV
Rapid
Repolarization
phase
Na+
Phase zero
depolarization
0
open
3
Phase 4
depolarization
4
Resting
-80 mV
-90 mV
Na+ K+
Ca++ K+
K+
K+
OUTSIDE
MEMBRANE
INSIDE
Ca++
Na+
Atp
K+
Na+
Cardiac Action Potential (con’t)
Phase 2 - plateau phase




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
Normally blocks any premature stimulator signals (other muscle tissue
can accept additional stimulation and increase contractility in a
summation effect)
Corresponds to ST segment of the ECG.
Phase 3 – repolarization




K+ channels remain open,
Allows K+ to build up outside the cell, causing the cell to repolarize
K + channels finally close when membrane potential reaches appropriate
level
Corresponds to T wave on the ECG
Differences between nonpacemaker and
pacemaker cell action potentials
PCs - Slow, continuous depolarization during rest
Continuously moves potential towards threshold for a
new action potential (called a phase 4 depolarization)
Typical action potential in SA nodal cells
Typical action potential in AV nodal cells
Typical action potential in cardiac muscle
cells
Influence of diastolic membrane potential
on action potential upstroke rate in a given
cell:
‘Membrane Responsiveness’
Mechanisms of Cardiac Arrhythmias
Result from disorders of impulse
formation, conduction, or both
Causes of arrhythmias




Cardiac ischemia
Excessive discharge or sensitivity to
autonomic transmitters
Exposure to toxic substances
Unknown etiology
Disorders of impulse formation
No signal from the pacemaker site
Development of an ectopic pacemaker



May arise from conduction cells (most are capable of
spontaneous activity)
Usually under control of SA node  if it slows down too much
conduction cells could become dominant
Often a result of other injury (ischemia, hypoxia)
Development of oscillatory afterdepolariztions


Can initiate spontaneous activity in nonpacemaker tissue
May be result of drugs (digitalis, norepinephrine) used to treat
other cardiopathologies
Afterdepolarizations
b) Trigerred automaticity
+30 mV
0 mV
Early After
Depolarisation
(EAD)
-80 mV
-90 mV
b) Trigerred automaticity
+30 mV
0 mV
Delayed After
Depolarisation
(DAD)
-80 mV
-90 mV
Intracellular cal. Overload (Ischemia
reperfusion, adr.stress, digitalis intoxication or
Regulation by autonomic tone
Parasympathetic/Vagus Nerve
stimulation:
• Ach binds to M2 receptors
• Activate Ach dependent outward K+
conductance (thus hyperpolarisation)
• ↓ phase 4 AP
Sympathetic stimulation:
• Activation of β1 receptors
• Augmentation of L-type Ca2+ current
• Phase 4 AP more steeper
Disorders of impulse conduction
May result in


Bradycardia (if have AV block)
Tachycardia (if reentrant circuit occurs)
Reentrant
circuit
Antiarrhythmic drugs
Biggest problem – antiarrhythmics can
cause arrhythmia!


Example: Treatment of a non-life threatening
tachycardia may cause fatal ventricular
arrhythmia
Must be vigilant in determining dosing, blood
levels, and in follow-up when prescribing
antiarrhythmics
Vaughan Williams Classification of
Antiarrhythmic Drugs
I. Drugs with direct membrane action (e.g., Na channel
blockade
A. moderate phase 0 depression
B. minimal phase 0 depression, usually shorten repolarization
C. marked phase 0 depression, little effect on repolarization
II. Sympatholytic drugs
III. Drugs that prolong repolarization
IV. Calcium channel blockers
For a less arbitrary classification based on arrhythmogenic
mechanisms and potentially vulnerable parameters, see the
report of the Task Force of the Working Group on
Antiarrhythmias of the European Society of Cardiology,
Circulation 84: 1831-1851, 1991
Classification of antiarrhythmics
(based on mechanisms of action)
Class I – blocker’s of fast Na+ channels

Subclass IA
Cause moderate Phase 0 depression
Prolong repolarization
Increased duration of action potential
Includes



Quinidine – 1st antiarrhythmic used, treat both atrial and
ventricular arrhythmias, increases refractory period
Procainamide - increases refractory period but side
effects
Disopyramide – extended duration of action, used only
for treating ventricular arrthymias
Quinidine decreases membrane
responsiveness
(moderate inhibition of Na channels)
Quinidine
Classification of antiarrhythmics
(based on mechanisms of action)

Subclass IB
Weak Phase 0 depression
Shortened depolarization
Decreased action potential duration
Includes



Lidocane (also acts as local anesthetic) – blocks Na+
channels mostly in ventricular cells, also good for
digitalis-associated arrhythmias
Mexiletine - oral lidocaine derivative, similar activity
Phenytoin – anticonvulsant that also works as
antiarrhythmic similar to lidocane
Lidocaine decreases membrane responsiveness
(selective inhibition of Na channels in depolarized
cells)
Lidocaine
Classification of antiarrhythmics
(based on mechanisms of action)

Subclass IC
Strong Phase 0 depression
No effect of depolarization
No effect on action potential duration
Includes


Flecainide (initially developed as a local anesthetic)
Slows conduction in all parts of heart,
Also inhibits abnormal automaticity
Propafenone
Also slows conduction
Weak β – blocker
Also some Ca2+ channel blockade
Class IC antiarrhythmics: major inhibition of
membrane responsiveness
(major inhibition of Na channels)
Flecainide or encainide
Classification of antiarrhythmics
(based on mechanisms of action)
Class II – β–adrenergic blockers

Based on two major actions
1) blockade of myocardial β–adrenergic receptors
2) Direct membrane-stabilizing effects related to Na+ channel blockade

Includes
Propranolol




causes both myocardial β–adrenergic blockade and membranestabilizing effects
Slows SA node and ectopic pacemaking
Can block arrhythmias induced by exercise or apprehension
Other β–adrenergic blockers have similar therapeutic effect
Metoprolol
Nadolol
Atenolol
Acebutolol
Pindolol
Stalol
Timolol
Esmolol
beta-blockers (class II)
Decrease cardiac automaticity and contractility, partly
by blocking beta-adrenergic receptors (& partly by
direct effects on cardiac cell membranes).
Antagonize the effects of catecholamines on Ca
channels (reduce automaticity and slow conduction in
partially depolarized cells and decrease myocardial
contractility)
Useful in supraventricular arrhythmias
Increase effective refractory period of AV node
AV block, asystole, sudden withdrawal can
precipitate angina, arrhythmias or myocardial
infarction
Contraindicated in asthma (relatively for beta-1
selective), may mask tachycardia of hypoglycemia,
CNS effects
Classification of antiarrhythmics
(based on mechanisms of action)
Class III – K+ channel blockers



Developed because some patients negatively
sensitive to Na channel blockers (they died!)
Cause delay in repolarization and prolonged
refractory period
Includes
Amiodarone – prolongs action potential by delaying K+ efflux
but many other effects characteristic of other classes
Ibutilide – slows inward movement of Na+ in addition to
delaying K + influx.
Bretylium – first developed to treat hypertension but found to
also suppress ventricular fibrillation associated with
myocardial infarction
Dofetilide - prolongs action potential by delaying K+ efflux
with no other effects
amiodarone (Class III)
(but also has Class I, II and IV effects)
A ‘dirty drug’, inhibits K channels, (delays
repolarization), Na channels and Ca channels (slight),
blocks beta-receptors non-competitively, blocks alpha
receptors, potent suppressor of ectopic automaticity
(only rarely causes torsades des pointes), and some
vagolytic effects.
Approved for ventricular tachycardia, ventricular
fibrillation and paroxysmal supraventricular
tachycardia, used in other arrhythmias as well; has
anti-anginal properties
Adverse reactions (too many to list) occur in about
70% of patients, sufficient to cause discontinuation in
5-20%.
Extremely long, biphasic, half life (initial about 10
Amiodarone: selected adverse reactions
(far too many to list)
ARDS
Ataxia
AV block
Bronchiolitis
obliterans
Dyspnea
Epididymitis
Heart failure
Hepatitis
Hyper/hypothyroidism
Macular degeneration
Optic neuritis
Pancreatitis
Peripheral neuropathy
Pneumonitis
QT prolongation
Sinus bradycardia
Thrombocytopenia
Torsade de pointes
Toxic epidermal
necrolysis
Vasculitis
Classification of antiarrhythmics
(based on mechanisms of action)
Class IV – Ca2+ channel blockers


slow rate of AV-conduction in patients with
atrial fibrillation
Includes
Verapamil – blocks Na+ channels in addition to
Ca2+; also slows SA node in tachycardia
Diltiazem
verapamil (class IV)
Blocks mainly L-type calcium channels
Decreases SA and Purkinje fiber automaticity,
slows conduction through and increases
refractory period of AV node
Useful mainly in supraventricular arrhythmias
or ventricular arrhythmias caused by coronary
spasm
GI disturbances, cardiac toxicity including
heart failure, AV block
diltiazem (class IV)
Blocks mainly L-type calcium channels
Decreases SA and Purkinje fiber automaticity,
slows conduction through and increases
refractory period of AV node
Useful mainly in supraventricular arrhythmias
or ventricular arrhythmias caused by coronary
spasm
GI disturbances, cardiac toxicity, including
heart failure, AV block
Antiarrhythmic drugs: a common theme
Effective antiarrhythmic drugs increase the
refractory period compared to action potential
duration: ERP/APD
Relatively speaking, this gives ‘more time’ for recovery
of membrane potential and makes slow conduction
less likely. Slow conduction is a formula for disaster.
+30 mV
Possible MOA of antiarrythmic agents
1
2
0 mV
RATE
0
SLOPE
3
THRESHOLD POTENTIAL
-80 mV
4
Effective Refractory Period
-90 mV
RMP
Na+ K+
Ca++ K+
OUTSIDE
MEMBRANE
INSIDE
Na+ Ca++ K+
Ca++
K+
Na+
Atp
K+
Na+
Magnesium
• Its mechanism of action is unknown but
may influence Na+/K+ATPase, Na+
channels, certain K+ channels & Ca2+
channels
• Use: Digitalis induced arrhythmias if
hypomagnesemia present, refractory
ventricular tachyarrythmias, Torsade de
pointes even if serum Mg2+ is normal
• Given 1g over 20mins
Classification of
Antiarrhythmic Agents
IA
Quinidine
Procainamide
Disopyramide
IC
Flecainide
Propafenone
Encainide
IB
Lidocaine
Mexiletine
Tocainide
I?
Moricizine
Classification of
Antiarrhythmic Agents
II
Beta-adrenergic blockers
III
Amiodarone
Dronedarone
Sotalol
IV
Calcium channel blockers
Ibutilide
Dofetilide
Bretylium
Diltiazem & Verapamil
Classification of
Antiarrhythmic Agents
Digoxin
Adenosine
Generic
Brandname
Disopyramide
Mexiletine
Flecainide
Propafenone
Amiodarone
Dronedarone
Esmolol
Sotalol
Ibutilide
Dofetilide
Digoxin
Adenosine
Norpace
Mexitil
Tambocor
Rythmol
Cordarone, Pacerone
Multaq
Brevibloc
Betapace, Sorine
Corvert
Tikosyn
Lanoxin, Digitek
Adenocard
Ia’s create a double block
Ib’s take away the block
What about Ic’s?
- They have no effect on action
potential duration
Quinidine
• Type IA antiarrhythmic
• Indicated for atrial fibrillation and
ventricular tachycardias
Quinidine
Adverse Effects
• GI irritation
• Bitter taste
• Hepatitis & other hepatic conditions
• Rash & drug fever
• Thrombocytopenia
• Cinchonism
•
•
•
•
Tinnitus
Blurred vision
Headaches
Dizziness
Quinidine
• Different salts
•
•
•
•
•
•
Sulfate (83%)PO,SR
Gluconate (62%)SR,IV
Hepatically eliminated (t1/2 ~6-8 hr)
Increases digoxin & warfarin levels
IV dosage form – hemodynamic instability
Some concern when IV verapamil or
diltiazem is given to a patient on quinidine
Procainamide
Type IA antiarrhythmic
Indicated for acute conversion of
ventricular & atrial dysrhythmias
Procainamide
• Short half-life (~3 hours)
• 6-h & 12-h SR dosage forms once existed
• 50% hepatically metabolized, mostly to
NAPA (fast/slow acetylators)
• NAPA (as w/ 50% of PA) is renally
eliminated
• Causes drug-induced SLE
Procainamide
Adverse Effects
• Gastrointestinal
• CNS
• Fever
• Rash
• Blood dyscrasias
• Some negative inotropic properties
• Hypotension w/ rapid IV infusions
Procainamide
Dosing


Acute: 17 mg/kg @ 20 mg/min (50 mg/min, if
urgent)
Infusion: 1-4 mg/min (depends on renal fxn)
Metabolism

NAPA produced (a renally eliminated active
metabolite of procainamide)

Toxicity if NAPA levels exceed 20 mg/L
Disopyramide
• Type IA antiarrhythmic
• Indicated in atrial and ventricular
arrhythmias
Disopyramide
• Concentration-dependent plasma protein
binding
• An increase in dosage rate results in an
increase in the percentage of disopyramide
that is unbound
• Increased unbound drug allows for
enhanced clearance
• As a result, increasing the dosage rate
results in a less than proportional increase
in total drug concentration
Dosage Rate
Disopyramide
• Therefore, total drug concentrations have a
limited role in assisting on how much to
adjust the dosage of disopyramide due to its
concentration-dependent plasma protein
binding
• Total drug concentrations can be used to
document a patient’s “effective” drug
concentration once efficacy has been
demonstrated
Disopyramide
Adverse Effects
• Gastrointestinal
• Negative inotrope
• Anticholinergic adverse effects
•
•
•
•
Dry mouth
Blurred vision
Constipation
Urinary hesitation
Disopyramide
• Elimination
•
•
~50% hepatic
~50% renal
• Half-life
•
~7 hours
Disopyramide
• Used in neurocardiogenic syncope &
hypertrophic hearts
•
•
Anticholinergic properties
Negative inotropic properties
Lidocaine
• Type IB antiarrhythmic
• Indicated in acute treatment and
prevention of ventricular dysrhythmias
Lidocaine
• Type IB antiarrhythmic
• Indicated in acute treatment and
prevention of ventricular dysrhythmias
Lidocaine
Half Life
 Initially, 1.5 hours; but increases
to 3.0 hours 2-3 days into therapy
Lidocaine reduces its own rate of
metabolism
Lidocaine
Toxicity most often manifested by:
Nausea
Drowsiness
Dizziness
Confusion
Tremors
Facial numbness
Paresthesias
Peripheral
numbness
Altered speech Seizures
Lidocaine
Dosing


1.0-1.5 mg/kg IVP over 1-2 min;
repeat every 5-10 min with 0.5-0.75
mg/kg, as needed, until 3 mg/kg
total dose
Typical maintenance dose: 1.0-4.0
mg/min
Use lower rate with CHF
Mexiletine
• Type IB antiarrhythmic
• Only indicated to prevent ventricular
arrhythmias
Mexiletine
Adverse Effects
• Extremely GI irritating
• Altered CNS functioning
• Hepatically metabolized
•
Half-life: 6-12 hours
Flecainide
• Type IC antiarrhythmic
• Since it is very proarrhythmic:
•
Generally used only for atrial
dysrhythmias
Flecainide
• Very proarrhythmic in patients with:
• CAD
• CHF
• Ventricular dysrhythmias
• Used primarily in atrial fibrillation when
concerns for proarrhythmias are not
present
Flecainide
Adverse Effects
• Gastrointestinal
• CNS
• Negative inotrope
Pharmacokinetics
• Mostly hepatic clearance (60%); some renal (30%)
• Half-life: ~20 hours
Propafenone
• Type IC with some beta-blocking
properties
• Primarily used for atrial
dysrhythmias
•
Rarely, ventricular
Propafenone
Adverse Effects
• Gastrointestinal
• CNS
• Negative inotrope
• Metallic taste
Propafenone
• Non-linear absorption & elimination
•
Bioavailability increases w/ higher doses
• IR and SR dosages are NOT bioequivalent

•
SR has reduced bioavailability
Clearance decreases w/ higher doses
• Hepatic elimination
•
•
Active metabolites
Extensive (90%) & Slow (10%) metabolizers
• Increases digoxin levels
Sotalol
• Non-selective beta-blocker with type
III antiarrhythmic activity
• Used to acutely treat and prevent
atrial & ventricular dysrhythmias
Sotalol
• Renally eliminated
• Negative inotrope
• Beta-blocker concerns
• Torsade de pointes
Sotalol
• Renally eliminated
• Negative inotrope
• Beta-blocker concerns
• Torsade de pointes
•
•
•
Do not initiate if QT > 450 msec
Desire QT < 500 msec for first 3 days
Desire QT < 520 msec thereafter
Sotalol
Now available parenterally
•
Indications
• Ventricular tachyarrhythmias
• Atrial fibrillation/flutter
•
•
75 mg IV = 80 mg po
Give dose over 5 hours
Amiodarone
Type III antiarrhythmic agent
Contains alpha- & beta-receptor
blocking properties as well as
sodium-, potassium-, & calciumchannel blocking properties
Indicated for ventricular & atrial
dysrhythmias
Amiodarone
Large volume of distribution
Half-life: 30 - 100 days
Metabolized primarily by CYP 3A4
Active metabolite: Ndesethylamiodarone

Half-life: ~60 days
Amiodarone
Toxicities
CNS
GI
Skin
Liver
Thyroid
Bradycardia
Cornea deposits
Optic neuropathy
Photosensitivity
Pulmonary fibrosis
Baseline labs



Thyroid
(recheck every 6 mths)
Liver
(recheck every 6 mths)
Pulmonary (annual CXR)
Arch Intern Med 2000;160:1741-8
Amiodarone
An allergy to iodine (but not contrast dye)
is a contraindication to using amiodarone
Amiodarone
An oral dosing protocol




15 mg/kg/day x 1 week (~400 mg TID)
10 mg/kg/day x 2 weeks (~400 mg BID)
5 mg/kg/day (~400 mg QD)
Eventually reduce to 100-200 mg daily
Oral bioavailability: ~50%
Amiodarone
General IV load



150 mg over 10 minutes
1 mg/min x 6 hours
0.5 mg/min x 18 hours or longer
Monitor heart rate & blood pressure
Ventricular fibrillation

300 mg IVP; may repeat w/ 150 mg IVP
Ventricular tachycardia

150 mg over 10 min; repeat as needed to a total of
2.2 gm in 24 hours
A Sampling of Drug
Interactions
Warfarin
Digoxin
Metoprolol
Quinidine
Procainamide
Disopyramide
Flecainide
Theophylline
Phenytoin
Simvastatin
Cyclosporine
Methotrexate
Dronedarone
A “less toxic” amiodarone
Half-life: 13-19 hours
Only FDA-approved for atrial
fibrillation/flutter

Not as effective as amiodarone
Dronedarone
GI irritation
Prolongs QT interval
Negative inotrope

Contraindicated in:
 NYHA IV
 Acute CHF exacerbations
Dronedarone
Metabolized by CYP 3A4
Inhibits CYPs 3A4 & 2D6 and P-gp
Increases digoxin levels
Dosing: 400 mg BID
Ibutilide
Pharmacology

Type III antiarrhythmic
Indicated for acute conversion of atrial
flutter a/o fibrillation

Proarrhythmic

More so in patients w/ CHF
If ibutilide fails to convert, it may at least
enhance the response to electrocardioversion
Ibutilide
Monitor for proarrhythmias,
including torsade de pointes, for 4-6
hours after dosing and until QT is
not prolonged
Hepatically cleared

Half-life: ~6 hours
Ibutilide
Approved Dosing


1 mg (0.01 mg/kg < 60 kg) over 10 min;
repeat, if needed, after 10 min
Preload with magnesium (?)
Alternative Method of Dosing



2 mg (placed in 50 cc D5W) over 30 minutes
Stop infusion when patient converts
Preload with magnesium (?)
Dofetilide
Oral “relative” to ibutilide
Indicated for atrial fibrillation/flutter


Conversion
Maintenance
Proarrhythmic

Torsade de pointes
Need “certification” to prescribe &
dispense
Dofetilide
To become “certified” to dispense
dofetilide, visit:
www.TIKOSYN.com
Click on the prompt that allows you to become a
Confirmed Prescriber
and follow the instructions
Dofetilide
Clearance

Hepatic
 CYP 3A4

Renal
 Renal tubular secretion
Dofetilide
Drug Interaction Precautions

CYP 3A4 inhibitors
Erythro, Clarithro, Grapefruit, Conazoles, SSRIs

Cationic renal secretion inhibitors
Triamterene, Metformin, Amiloride

QT-prolonging medications
Dofetilide
Contraindications



QTc > 440 msec (> 500 msec w/ VCD)
CrCl < 20 mL/min
Drugs
Cimetidine
Trimethoprim (incl. Bactrim)
Verapamil
Ketoconazole
Prochlorperazine
Megestrol
HCTZ
Dofetilide
Generally, wait three half-lives after stopping
previous antiarrhythmic before starting
dofetilide

With amiodarone, wait three months (or until
amiodarone concentration < 0.3 mcg/mL)
Wait 48 hours after stopping dofetilide before
starting another antiarrhythmic
Dofetilide
Considerations when initiating therapy:
Hospitalization for 3 days
Continuous EKG monitoring
Determine baseline CrCl & QTc
Confirm that patient has method of obtaining
medication from a “certified” pharmacy upon
discharge

If patient cannot immediately obtain dofetilide upon
discharge, assure that patient can obtain 7-day “bridge”
therapy from the hospital
Dofetilide
Starting doses
CrCl
Dose
> 60 mL/min
40 - 60 mL/min
20 - 39 mL/min
500 mcg BID
250 mcg BID
125 mcg BID
Dofetilide
Check QTc 2-3 hours after 1st
dose
Decrease future doses by 50%
if:


QTc increased by 15% from baseline
QTc > 500 msec (> 550 msec if VCD)
Dofetilide
With each subsequent dose, check QTc
2-3 hours after administration
Discontinue dofetilide if QTc > 500
msec
(> 550 msec if VCD)
Digoxin in CHF
• Loading dose not essential for CHF
• Improves CHF morbidity, but not
mortality
• Drug levels for CHF: 0.7-0.9 ng/mL
Digoxin
• Vagolytic effects slow heart rate and
conduction through AV node
• Used to slow the ventricular rate of
atrial fibrillation
• Used to interrupt reentry in PSVT
Digoxin
• Loading dose
•
•
About 0.0125 mg/kg of LBW
Give 50% now, then two doses of 25%; each
separated by 4-6 hours
• Severe renal failure reduces the Vd; thus, a
smaller loading dose is required
• Therapeutic range: 1–2 mcg/L
Digoxin – General Facts
•
•
•
•
Half-life: 36 hours or longer
Long distribution phase (6-12 hours)
Primarily renal elimination
Important Drug interactions
•
•
•
•
Verapamil
Quinidine
Amiodarone
Propafenone
• Effects reversed with Digibind & Digifab
•
Digibind/fab use impacts digoxin levels
Drug Distribution
Cp
12 h
Time
Digoxin
Adverse Effects
Gastrointestinal
Dysrhythmias
Central nervous system
Visual
DIGOXIN TOXICITY
Precipitating Factors
Hypokalemia
Hypomagnesemia
Hypercalcemia
Hypothyroidism
Amyloidosis
DIGOXIN DRUG INTERACTIONS
Increased concentrations
Quinidine
Verapamil
Amiodarone
Dronedarone
Propafenone
Ranolazine
Carvedilol
Cyclosporine
PPI’s
Macrolides
Decreased concentrations
Acarbose/Miglitol
Bile acid sequestrants
Adenosine
Rapid IV push (6 mg over 1-2 sec)
When using IV line, flush with saline
If no effect after 1-2 min, give 12 mg; may
repeat 12 mg dose once
Short-term adverse effects:
Flushing
Shortness of breath
Chest discomfort
Asystole
Effects potentiated by dipyridamole & CBZ
DO NOT use in heart transplant patients
Adenosine
The effects of adenosine are
antagonized by methylxanthines
Theophylline
Caffeine
MEDICATION COMPARISON
Medication
Quinidine
Disopyramide*
Mexiletine
Flecainide*
Propafenone*
Amiodarone
Sotalol*
*Negative
Efficacy
2
1.5
1
2o
2?
4
2.5
Inotrope
oProarrhythmia risk
?Has potential for proarrhythmia?
Side Effects
Mod
High
Mod
V. Low
Low-Mod
High
Low-Mod
Toxicity
Mod
Low
Low
Low
Low
V. High
Low