CLINICAL PHARMACOLOGY OF ANTIARRHYTHMIC MEDICATIONS

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CLINICAL PHARMACOLOGY OF ANTIARRHYTHMIC
MEDICATIONS

• Vincent F. Mauro, PharmD, FCCP

Professor of Clinical Pharmacy and Adjunct
Professor of Medicine The University of Toledo
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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

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Automaticity
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Reentry-induced dysrhythmia
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Classification of Antiarrhythmic Agents

• IA Quinidine IC Flecainide
• Procainamide Propafenone
• Disopyramide Encainide
• IB Lidocaine I? Moricizine
• Mexiletine
• Tocainide

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Classification of Antiarrhythmic Agents

• II Beta-adrenergic blockers
• III Amiodarone Ibutilide
• Dronedarone Dofetilide
• Sotalol Bretylium
• IV Calcium channel blockers
• Diltiazem Verapamil

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Classification of Antiarrhythmic Agents

• Digoxin
• Adenosine

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• Generic Brandname
• Disopyramide Norpace
• Mexiletine Mexitil
• Flecainide Tambocor
• Propafenone Rythmol
• Amiodarone Cordarone, Pacerone
• Dronedarone Multaq
• Esmolol Brevibloc
• Sotalol Betapace, Sorine
• Ibutilide Corvert
• Dofetilide Tikosyn
• Digoxin Lanoxin, Digitek
• Adenosine Adenocard

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Type Ix
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Type Ia
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Type Ib
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Type Ic
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Ias create a double block
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Ibs take away the block
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What about Ics? - They have no effect on action
potential duration
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Type II IV
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Type III
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CLINICAL INDICATIONS

• Medication Ventricular Atrial
• QuinidinePO,SR,IV X X
• Procainamide IV X X
• DisopyramidePO,SR X X
• LidocaineIV X -
• MexiletinePO X -
• FlecainidePO X!! X
• PropafenonePO,SR X X

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CLINICAL INDICATIONS

• Medication Ventricular Atrial
• Beta-blockersPO,SR,IV E AV
• AmiodaronePO,IV X X
• DronedaronePO - X
• SotalolPO,IV X X/AV
• DofetilidePO ? X
• IbutilideIV ? AF/Fl
• Calcium channel blockersPO,SR,IV E? AV

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CLINICAL INDICATIONS

• Medication Ventricular Atrial
• DigoxinPO,IV - AV
• AdenosineIV - PSVT

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Quinidine

• Type IA antiarrhythmic
• Indicated for atrial fibrillation and ventricular
  tachycardias

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Quinidine

• Adverse Effects
• GI irritation
• Bitter taste
• Hepatitis other hepatic conditions
• Rash drug fever
• Thrombocytopenia
• Cinchonism
• Tinnitus
• Blurred vision
• Headaches
• Dizziness

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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

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Procainamide

• Type IA antiarrhythmic
• Indicated for acute conversion of ventricular
  atrial dysrhythmias

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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

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Procainamide

• Adverse Effects
• Gastrointestinal
• CNS
• Fever
• Rash
• Blood dyscrasias
• Some negative inotropic properties
• Hypotension w/ rapid IV infusions

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Procainamide

• Dosing
• Acute 17 mg/kg _at_ 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

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Disopyramide

• Type IA antiarrhythmic
• Indicated in atrial and ventricular arrhythmias

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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

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Concentration at Steady State
Dosage Rate
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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

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Disopyramide

• Adverse Effects
• Gastrointestinal
• Negative inotrope
• Anticholinergic adverse effects
• Dry mouth
• Blurred vision
• Constipation
• Urinary hesitation

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Disopyramide

• Elimination
• 50 hepatic
• 50 renal
• Half-life
• 7 hours

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Disopyramide

• Used in neurocardiogenic syncope hypertrophic
  hearts
• Anticholinergic properties
• Negative inotropic properties

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Lidocaine

• Type IB antiarrhythmic
• Indicated in acute treatment and prevention of
  ventricular dysrhythmias

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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

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Lidocaine

• Toxicity most often manifested by
• Nausea Dizziness
• Drowsiness Confusion
• Tremors Facial numbness
• Paresthesias Peripheral numbness
• Altered speech Seizures

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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

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Mexiletine

• Type IB antiarrhythmic
• Only indicated to prevent ventricular arrhythmias

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Mexiletine

• Adverse Effects
• Extremely GI irritating
• Altered CNS functioning
• Hepatically metabolized
• Half-life 6-12 hours

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Flecainide

• Type IC antiarrhythmic
• Since it is very proarrhythmic
• Generally used only for atrial dysrhythmias

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Flecainide

• Very proarrhythmic in patients with
• CAD
• CHF
• Ventricular dysrhythmias
• Used primarily in atrial fibrillation when
  concerns for proarrhythmias are not present

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Flecainide

• Adverse Effects
• Gastrointestinal
• CNS
• Negative inotrope
• Pharmacokinetics
• Mostly hepatic clearance (60) some renal (30)
• Half-life 20 hours

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Propafenone

• Type IC with some beta-blocking properties
• Primarily used for atrial dysrhythmias
• Rarely, ventricular

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Propafenone

• Adverse Effects
• Gastrointestinal
• CNS
• Negative inotrope
• Metallic taste

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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

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Sotalol

• Non-selective beta-blocker with type III
  antiarrhythmic activity
• Used to acutely treat and prevent atrial
  ventricular dysrhythmias

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Sotalol

• Renally eliminated
• Negative inotrope
• Beta-blocker concerns
• Torsade de pointes

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Sotalol

• Renally eliminated
• Negative inotrope
• Beta-blocker concerns
• Torsade de pointes
• Do not initiate if QT gt 450 msec
• Desire QT lt 500 msec for first 3 days
• Desire QT lt 520 msec thereafter

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Sotalol

• Now available parenterally
• Indications
• Ventricular tachyarrhythmias
• Atrial fibrillation/flutter
• 75 mg IV 80 mg po
• Give dose over 5 hours

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Amiodarone

• Type III antiarrhythmic agent
• Contains alpha- beta-receptor blocking
  properties as well as sodium-, potassium-,
  calcium- channel blocking properties
• Indicated for ventricular atrial dysrhythmias

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Amiodarone

• Large volume of distribution
• Half-life 30 - 100 days
• Metabolized primarily by CYP 3A4
• Active metabolite N-desethylamiodarone
• Half-life 60 days

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Amiodarone

• Toxicities
• CNS Liver Cornea deposits
• GI Thyroid Optic neuropathy
• Skin Bradycardia Photosensitivity
• Pulmonary fibrosis
• Baseline labs
• Thyroid (recheck every 6 mths)
• Liver (recheck every 6 mths)
• Pulmonary (annual CXR)
• Arch Intern Med 20001601741-8

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Amiodarone

• An allergy to iodine (but not contrast dye) is a
  contraindication to using amiodarone

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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

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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

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A Sampling of Drug Interactions

• Warfarin
• Digoxin
• Metoprolol
• Quinidine
• Procainamide
• Disopyramide

• Flecainide
• Theophylline
• Phenytoin
• Simvastatin
• Cyclosporine
• Methotrexate

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Dronedarone

• A less toxic amiodarone
• Half-life 13-19 hours
• Only FDA-approved for atrial fibrillation/flutter
• Not as effective as amiodarone

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Dronedarone

• GI irritation
• Prolongs QT interval
• Negative inotrope
• Contraindicated in
• NYHA IV
• Acute CHF exacerbations

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Dronedarone

• Metabolized by CYP 3A4
• Inhibits CYPs 3A4 2D6 and P-gp
• Increases digoxin levels
• Dosing 400 mg BID

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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

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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

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Ibutilide

• Approved Dosing
• 1 mg (0.01 mg/kg lt 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 (?)

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Dofetilide

• Oral relative to ibutilide
• Indicated for atrial fibrillation/flutter
• Conversion
• Maintenance
• Proarrhythmic
• Torsade de pointes
• Need certification to prescribe dispense

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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

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Dofetilide

• Clearance
• Hepatic
• CYP 3A4
• Renal
• Renal tubular secretion

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Dofetilide

• Drug Interaction Precautions
• CYP 3A4 inhibitors
• Erythro, Clarithro, Grapefruit, Conazoles, SSRIs
• Cationic renal secretion inhibitors
• Triamterene, Metformin, Amiloride
• QT-prolonging medications

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Dofetilide

• Contraindications
• QTc gt 440 msec (gt 500 msec w/ VCD)
• CrCl lt 20 mL/min
• Drugs
• Cimetidine
• Trimethoprim (incl. Bactrim)
• Verapamil
• Ketoconazole
• Prochlorperazine
• Megestrol
• HCTZ

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Dofetilide

• Generally, wait three half-lives after stopping
  previous antiarrhythmic before starting
  dofetilide
• With amiodarone, wait three months (or until
  amiodarone concentration lt 0.3 mcg/mL)
• Wait 48 hours after stopping dofetilide before
  starting another antiarrhythmic

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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

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Dofetilide

• Starting doses
• CrCl Dose
• gt 60 mL/min 500 mcg BID
• 40 - 60 mL/min 250 mcg BID
• 20 - 39 mL/min 125 mcg BID

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Dofetilide

• Check QTc 2-3 hours after 1st dose
• Decrease future doses by 50 if
• QTc increased by 15 from baseline
• QTc gt 500 msec (gt 550 msec if VCD)

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Dofetilide

• With each subsequent dose, check QTc
• 2-3 hours after administration
• Discontinue dofetilide if QTc gt 500 msec
• (gt 550 msec if VCD)

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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

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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

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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

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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

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Drug Distribution
Cp
Time
12 h
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DigoxinAdverse Effects

• Gastrointestinal
• Dysrhythmias
• Central nervous system
• Visual

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DIGOXIN TOXICITYPrecipitating Factors

• Hypokalemia
• Hypomagnesemia
• Hypercalcemia
• Hypothyroidism
• Amyloidosis

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DIGOXIN DRUG INTERACTIONS

• Increased concentrations
• Quinidine Ranolazine
• Verapamil Carvedilol
• Amiodarone Cyclosporine
• Dronedarone PPIs
• Propafenone Macrolides
• Decreased concentrations
• Acarbose/Miglitol
• Bile acid sequestrants

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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 Chest discomfort
• Shortness of breath Asystole
• Effects potentiated by dipyridamole CBZ
• DO NOT use in heart transplant patients

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Adenosine

• The effects of adenosine are antagonized by
  methylxanthines
• Theophylline
• Caffeine

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MEDICATION COMPARISON

• Medication Efficacy Side Effects
  Toxicity
• Quinidine 2 Mod Mod
• Disopyramide 1.5 High Low
• Mexiletine 1 Mod Low
• Flecainide 2o V. Low Low
• Propafenone 2? Low-Mod Low
• Amiodarone 4 High V. High
• Sotalol 2.5 Low-Mod Low
• Negative Inotrope
• oProarrhythmia risk
• ?Has potential for proarrhythmia?

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TORSADE DE POINTES Cardiovascular Agents

• Type IA
• Quinidine
• Procainamide
• Disopyramide
• Type III
• Sotalol
• Dronedarone
• Ibutilide
• Dofetilide
• Ranolazine

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TORSADE DE POINTESAntimicrobials

• Pentamidine
• Macrolides
• Erythromycin Clarithromycin
• Ketolides
• Telithromycin
• Fluoroquinolones
• Moxifloxacin

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TORSADE DE POINTESNon-Cardiovascular Agents

• Antipsychotics
• Antidepressants
• Vasopressin
• Tacrolimus
• Droperidol
• Tamoxifen

• Methadone
• Chloral hydrate
• Triptans
• Cyclobenzaprine
• Apomorphine
• Vardenafil
• Posaconazole

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TORSADE DE POINTESDiscontinued Agents

• Terfenadine/Astemizole
• Cisapride
• Gatifloxacin/Grepafloxacin/Sparfloxacin
• Probucol
• Bepridil

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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