Transcript Antiarrhythmic Agents - University of Toledo

CLINICAL PHARMACOLOGY
OF ANTIARRHYTHMIC
MEDICATIONS
Vincent F. Mauro, PharmD, FCCP
Professor of Clinical Pharmacy
and
Adjunct Professor of Medicine
The University of Toledo
GOALS
To have a better understanding of:



The EPS properties of antiarrhythmics according
to their Vaughan-Williams classification
Important pharmacotherapeutic issues related to
antiarrhythmic use
The causes & treatment of torsade de pointes
Automaticity
Reentry-induced dysrhythmia
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
Type Ix
Type Ia
Type Ib
Type Ic
Ia’s create a double block
Ib’s take away the block
What about Ic’s?
- They have no effect on action
potential duration
Type II & IV
Type III
CLINICAL INDICATIONS
Medication
Ventricular
Atrial
QuinidinePO,SR,IV
Procainamide IV
DisopyramidePO,SR
X
X
X
X
X
X
LidocaineIV
MexiletinePO
X
X
-
FlecainidePO
PropafenonePO,SR
X!!
X
X
X
CLINICAL INDICATIONS
Medication
Ventricular
Atrial
Beta-blockersPO,SR,IV
E
AV
AmiodaronePO,IV
DronedaronePO
SotalolPO,IV
DofetilidePO
IbutilideIV
X
X
?
?
X
X
X/AV
X
AF/Fl
Calcium channel blockersPO,SR,IV
E?
AV
CLINICAL INDICATIONS
Medication
DigoxinPO,IV
AdenosineIV
Ventricular
-
Atrial
AV
PSVT
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
 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
Paresthesias
Altered speech
Facial numbness
Peripheral numbness
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
•
•
Hepatic elimination
•
•
•
Clearance decreases w/ higher doses
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: N-desethylamiodarone

 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
 Flecainide
 Digoxin
 Theophylline
 Metoprolol
 Phenytoin
 Quinidine
 Simvastatin
 Procainamide
 Cyclosporine
 Disopyramide
 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
become “certified” to dispense
dofetilide, visit:
www.TIKOSYN.com
 To
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,
 Cationic
Clarithro, Grapefruit, Conazoles, SSRIs
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
TORSADE DE POINTES
Cardiovascular Agents
Type IA
 Quinidine
 Procainamide
 Disopyramide
Type III
 Sotalol
 Dronedarone
 Ibutilide
 Dofetilide
Ranolazine
TORSADE DE POINTES
Antimicrobials
Pentamidine
Macrolides
 Erythromycin
& Clarithromycin
Ketolides
 Telithromycin
Fluoroquinolones
 Moxifloxacin
TORSADE DE POINTES
Non-Cardiovascular Agents
Antipsychotics
Antidepressants
Vasopressin
Tacrolimus
Droperidol
Tamoxifen
Methadone
Chloral hydrate
Triptans
Cyclobenzaprine
Apomorphine
Vardenafil
Posaconazole
TORSADE DE POINTES
Discontinued Agents
Terfenadine/Astemizole
Cisapride
Gatifloxacin/Grepafloxacin/Sparfloxacin
Probucol
Bepridil
TORSADE DE POINTES
Treatment




Discontinue causative medication
Correct hypokalemia & hypomagnesemia
Give magnesium 1-2 grams IV
To prevent subsequent episodes, increase
heart rate until cause of TdP is corrected
and/or cleared from the body
 Temporary
pacemaker
 Isoproterenol
Cardioversion is only indicated when patient
becomes hemodynamically compromised