anti-arrhythmic agents prcl 628: medical pharmacology robert j. didomenico, pharmd, fccp clinical...
TRANSCRIPT
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.
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.
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
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