Anti-Arrhythmic AgentsPRCL 628: Medical Pharmacology

Robert J. DiDomenico, PharmD, FCCP Clinical Associate Professor

Cardiovascular Clinical Pharmacist

 OBJECTIVES

For each of the anti-arrhythmic drugs, students should be able to:

1. Describe the mechanism of action.

2. Compare and contrast the pharmacokinetic and drug interaction

profiles within each class.

3. Compare and contrast the clinical effects.

4. List the common and/or serious adverse effects.

Anti-Arrhythmic AgentsPRCL 628: Medical Pharmacology

Required Reading:

1. Hume JR, Grant AO. Chapter 14. Agents Used in Cardiac Arrhythmias. In: Katzung BG, Masters SB, Trevor AJ, eds. Basic & Clinical Pharmacology. 12th ed. New York: McGraw-Hill; 2012. http://www.accessmedicine.com/content.aspx?aID=55822293.

 

Suggested Reading:

2. Sampson KJ, Kass RS. Chapter 29. Anti-Arrhythmic Drugs. In: Knollmann BC, ed. Goodman & Gilman's The Pharmacological Basis of Therapeutics. 12th ed. New York: McGraw-Hill; 2011. http://www.accessmedicine.com/content.aspx?aID=16668361.

“Antiarrhythmic drugs are toxins with occasional therapeutic side effects”

• Peter Buttrick, MD

Sampson KJ, Kass RS. Chapter 29. Anti-Arrhythmic Drugs. In: Knollmann BC, ed. Goodman & Gilman's The Pharmacological Basis of Therapeutics. 12th ed. New York: McGraw-Hill; 2011. http://www.accessmedicine.com/content.aspx?aID=16668361.

Mechanisms of ArrhythmiasArrhythmia Common

MechanismTherapy

Premature atrial, nodal, & ventricular

depolarizations

Unknown None

Atrial fibrillation Disorganized “functional” re-

entry

Control ventricular rate: AV nodal blockade

Maintain NSR: Class I & III AADs, ablation

Atrial flutter Disorganized “functional” re-

entry

Control ventricular rate: AV nodal blockade

Maintain NSR: Class I & III AADs, ablation

Atrial tachycardia Automaticity or re-entry

Control ventricular rate: AV nodal blockade

Maintain NSR: Class I & III AADs, ablation

AVNRT Re-entry within/near AV

node

AV nodal blockadeAblation

AVRT Re-entry(accessory pathway)

AV nodal blockadeAblation

Ventricular tachycardia

Re-entry ortriggered ICD, Class I & III AADs

Ventricular fibrillation Disorganized re-entry

ICD, Class I & III AADs

• Susceptible tissues include SA & AV nodes, His-Purkinje system, & cells that lack spontaneous pacemaker activity (e.g., ischemic ventricular cells)

• Stimuli• Beta-adrenergic stimulation• Hypokalemia• Mechanical stretch

Mechanisms of ArrhythmiasEnhanced Automaticity

Mechanisms of ArrhythmiasTriggered Activity

Sampson KJ, Kass RS. Chapter 29. Anti-Arrhythmic Drugs. In: Knollmann BC, ed. Goodman & Gilman's The Pharmacological Basis of Therapeutics. 12th ed. New York: McGraw-Hill; 2011. http://www.accessmedicine.com/content.aspx?aID=16668361.

Mechanisms of ArrhythmiasRe-Entry

Sanoski CA, Bauman JL. Chapter 25. The Arrhythmias. In: Wells BG, ed. Pharmacotherapy: A Pathophysiologic Approach. 8th ed. New York: McGraw-Hill; 2011. http://www.accesspharmacy.com/content.aspx?aID=7972803.

Pharmacologic Approaches to Terminating Tachyarrhythmias

1. Decrease automaticity of ectopic foci

2. Facilitate conduction (shorten refractory period) in an area of unidirectional block

3. Depress conduction (prolong refractory period) in either part of the re-entry circuit

http://www.cvpharmacology.com/antiarrhy/sodium-blockers.htm

V-W class

Drugs Ion channel ConductionVelocity

Refractory Period

Automaticity

Ia DisopyramideProcainamide

Quinidine

Na+(intermediate)

Ib LidocaineMexiletine

Na+(fast) /

Ic FlecainidePropafenone

Na+(slow)

Pharmacology of Antiarrhythmic Drugs

V-W class

Drugs Ion channel ConductionVelocity

Refractory Period

Automaticity

Ia DisopyramideProcainamide

Quinidine

Na+(intermediate)

Ib LidocaineMexiletine

Na+(fast) /

Ic FlecainidePropafenone

Na+(slow)

II Beta-

blockersCa++ (indirect)

Pharmacology of Antiarrhythmic Drugs

V-W class

Drugs Ion channel ConductionVelocity

Refractory Period

Automaticity

Ia DisopyramideProcainamide

Quinidine

Na+(intermediate)

Ib LidocaineMexiletine

Na+(fast) /

Ic FlecainidePropafenone

Na+(slow)

II Beta-

blockersCa++ (indirect)

III AmiodaroneDofetilide

DronedaroneIbutilideSotalol

K+

Pharmacology of Antiarrhythmic Drugs

http://www.cvpharmacology.com/antiarrhy/potassium-blockers.htm

V-W class

Drugs Ion channel ConductionVelocity

Refractory Period

Automaticity

Ia DisopyramideProcainamide

Quinidine

Na+(intermediate)

Ib LidocaineMexiletine

Na+(fast) /

Ic FlecainidePropafenone

Na+(slow)

II Beta-

blockersCa++ (indirect)

III AmiodaroneDofetilide

DronedaroneIbutilideSotalol

K+

IV DiltiazemVerapamil

Ca++

Pharmacology of Antiarrhythmic Drugs

Drug Bioavailability

(%)

Primary Elim

Route

Half-life CYP substrate

CYP inhibition

PGP inhibition

Amiodarone 22 – 88 Hepatic 15 – 100 d 3A4, 1A2, 2C19, 2D6

2C9, 2D6, 3A4, 1A2,

2C19

Yes

Dofetilide 85 – 95 RenalHepatic

6 – 10 hr 3A4 - No

Dronedarone 4 – 15 Hepatic 13 – 19 hr 3A4 2D6, 3A4 Yes

Flecainide 90 - 95 RenalHepatic

10 – 20 hr 2D6, 1A2 2D6 No

Ibutilide n/a HepaticRenal

~6 hr (2 – 12)

Unknown Unknown Unknown

Lidocaine n/a Hepatic 1.5 – 2 hr 1A2, 3A4, 2C9, 2A6,

2B6

1A2 No

Mexiletine 80 – 95 HepaticRenal

10 – 14 hr 1A2, 2D6 1A2 No

Propafenone 11 – 39 Hepatic 3 – 25 hr 1A2, 2D6, 3A4

1A2, 2D6 No

Sotalol 90 – 90 Renal 10 – 20 hr - - No

Sanoski CA, Bauman JL. Chapter 25. The Arrhythmias. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM, eds. Pharmacotherapy: A Pathophysiologic Approach. 8th ed. New York: McGraw-Hill; 2011. http://www.accesspharmacy.com/content.aspx?aID=7972803. Accessed August 7, 2013.

Drug Other Effects Adverse Events/Toxicity

Amiodarone Contains iodineBeta-blocker

CCB

Bradycardia, thyroid dysfunction, hepatotoxicity, pulmonary toxicity photosensitivity, GI disturbances

Disopyramide Anticholinergic Torsades de Pointes, heart failure, GI disturbances, glaucoma, urinary retention, dry mouth

Dofetilide - Torsades de Pointes

Dronedarone Beta-blockerCCB

Increased creatinine, GI disturbances

Flecainide - Ventricular tachycardia, headache, dizziness, visual changes

Ibutilide - QTc prolongation, ventricular tachycardia, Torsades de Pointes, hypotension

Lidocaine - CNS toxicity, seizures

Mexiletine - Lightheadedness, dizziness, anxiety, GI disturbances, tremor, visual changes

Propafenone Weak beta-blocker

Ventricular tachycardia, dizziness, GI disturbances

Sotalol Beta-blocker Torsades de Pointes, bradycardia, heart failure, bronchospasm

ACC/AHA/ESC Guidelines for the Management of Patients with Atrial Fibrillation. J Am Coll Cardiol 2001;38:1266.

CAST Investigators. N Engl J Med 1989;321:406-12.

Risk Factors for Ventricular Proarrhythmia with Antiarrhythmic Drugs

Class Ia & III Antiarrhythmic Drugs Class Ic Antiarrhythmic Drugs

Long QTc syndrome (baseline)(> 460ms)

Widened QRS (baseline)(> 120ms)

Structural heart disease Structural heart disease

Bradycardia Rapid ventricular response

High doses High doses

Excessive QTc prolongation (> 15% from baseline)

Excessive QRS widening (> 50% from baseline)

Electrolyte deficienciesLow K+ and/or Mg++

Drug Interactions• Diuretics• Other QT prolonging

drugs

Psychotropics• Haloperidol• Risperidone • Ziprasidone • Olanzapine • Quetiapine

Antidepressants• SSRIs• Tricyclic antidepressants

Anti-infectives• Macrolide antibiotics • Quinolone antibiotics• Bactrim• Azole antifungals

Methadone

Quinine

Promethazine

Tacrolimushttp://www.crediblemeds.org/everyone/composite-list-all-qtdrugs/

Examples of QTc Prolonging Drugs

Bauman JL. Eur Heart J 2001;3:K93-K100.

Avoid/Contraindicated• QTc prolonging drugs• Amiodarone, Dronedarone

• Strong CYP3A4 inhibitors

• Dofetilide• Verapamil• Cimetidine• Hydrochlorothiazide• Trimethoprim

• Propafenone, Flecainide• HIV protease inhibitors

Use caution• Amiodarone, Dronedarone

• Warfarin• Statins• Digoxin

• Propafenone• Strong CYP2D6 inhibitors• Moderate CYP3A4 inhibitors

• Flecainide• Moderate/strong CYP2D6

inhibitors

Common Antiarrhythmic Drug Interactions

• Itraconazole• Ketoconazole• Prochlorperazi

ne• Megestrol

Wann LS, et al. Circulation 2011;123:104-23.

Antiarrhythmic Drug Selection for Maintaining Normal Sinus Rhythm

No/Minimal Structural

Heart Disease

Hypertension Coronary ArteryDisease

Heart Failure

DronedaroneFlecainide

PropafenoneSotalol

Amiodarone

≠ LVHSubstantial

LVH

AmiodaroneDofetilide

CatheterAblation

DofetilideSotalol

AmiodaroneDofetilide

CatheterAblation

AmiodaroneDofetilide