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
Lidocaine Mexiletine Tocainide

IC

Flecainide Propafenone Encainide

Moricizine

IB

I?

Classification of Antiarrhythmic Agents

II III Beta-adrenergic blockers Amiodarone Dronedarone Sotalol Ibutilide Dofetilide Bretylium

IV

Calcium channel blockers

Diltiazem & Verapamil

Classification of Antiarrhythmic Agents

Digoxin

Adenosine

Generic
Disopyramide Mexiletine Flecainide Propafenone Amiodarone Dronedarone Esmolol Sotalol Ibutilide Dofetilide Digoxin Adenosine

Brandname
Norpace Mexitil Tambocor Rythmol Cordarone, Pacerone Multaq Brevibloc Betapace, Sorine Corvert Tikosyn Lanoxin, Digitek Adenocard

Type Ix

Type Ia

Type Ib

Type Ic

Ias create a double block

Ibs take away the block

What about Ics?

- They have no effect on action potential duration

Type II & IV

Type III

CLINICAL INDICATIONS
Medication
QuinidinePO,SR,IV Procainamide IV DisopyramidePO,SR LidocaineIV MexiletinePO FlecainidePO PropafenonePO,SR

Ventricular
X X X X X X!! X

Atrial
X X X X X

CLINICAL INDICATIONS
Medication
Beta-blockersPO,SR,IV AmiodaronePO,IV DronedaronePO SotalolPO,IV DofetilidePO IbutilideIV Calcium channel blockersPO,SR,IV

Ventricular
E X X ? ? E?

Atrial
AV X X X/AV X AF/Fl 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 if NAPA levels exceed 20 mg/L

metabolite of procainamide)
Toxicity

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 patients 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:

Dizziness Confusion

Nausea Drowsiness

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
maintenance dose: 1.0-4.0 mg/min Use lower rate with CHF

Typical

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 Active metabolites Extensive (90%) & Slow (10%) metabolizers

Hepatic elimination

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
Pulmonary

(recheck every 6 mths)

(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
300 150

mg IVP; may repeat w/ 150 mg IVP

Ventricular tachycardia
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 Flecainide Theophylline Phenytoin Simvastatin 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
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 tubular secretion

Renal

Dofetilide

Drug Interaction Precautions

CYP

3A4 inhibitors
Clarithro, Grapefruit, Conazoles, SSRIs Metformin, Amiloride

Erythro,

Cationic

renal secretion inhibitors medications

Triamterene,

QT-prolonging

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
> 60 mL/min 40 - 60 mL/min 20 - 39 mL/min

Dose
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: 12 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

Digibind/fab use impacts digoxin levels

Effects reversed with Digibind & Digifab

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 Acarbose/Miglitol Bile acid sequestrants Ranolazine Carvedilol Cyclosporine PPIs Macrolides

Decreased concentrations

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

Side Effects
Mod High Mod V. Low Low-Mod High Low-Mod

Toxicity
Mod Low Low Low Low V. High Low

Inotrope oProarrhythmia risk ?Has potential for proarrhythmia?

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