Transcript AADs pharmacology1

Anti-Arrhythmic Agents
PRCL 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 Agents
PRCL 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: McGrawHill; 2012. http://www.accessmedicine.com/content.aspx?aID=55822293.
Suggested Reading:
1.
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 Arrhythmias
Arrhythmia
Common
Mechanism
Therapy
Premature atrial, nodal, &
ventricular depolarizations
Unknown
None
Atrial fibrillation
Disorganized
Control ventricular rate: AV nodal blockade
“functional” re-entry Maintain NSR: Class I & III AADs, ablation
Atrial flutter
Disorganized
Control ventricular rate: AV nodal blockade
“functional” re-entry 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 blockade
Ablation
AVRT
Re-entry
(accessory pathway)
AV nodal blockade
Ablation
Ventricular tachycardia
Re-entry or
triggered
ICD, Class I & III AADs
Ventricular fibrillation
Disorganized
re-entry
ICD, Class I & III AADs
Mechanisms of Arrhythmias
Enhanced Automaticity
• 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 Arrhythmias
Triggered 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 Arrhythmias
Re-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
Pharmacology of Antiarrhythmic Drugs
V-W
class
Drugs
Ion channel
Conduction
Velocity
Refractory
Period
Automaticity
Ia
Disopyramide
Procainamide
Quinidine
Na+
(intermediate)



Ib
Lidocaine
Mexiletine
Na+
(fast)
/


Ic
Flecainide
Propafenone
Na+
(slow)



Pharmacology of Antiarrhythmic Drugs
V-W
class
Drugs
Ion channel
Conduction
Velocity
Refractory
Period
Automaticity
Ia
Disopyramide
Procainamide
Quinidine
Na+
(intermediate)



Ib
Lidocaine
Mexiletine
Na+
(fast)
/


Ic
Flecainide
Propafenone
Na+
(slow)



II
Betablockers
Ca++ (indirect)



Pharmacology of Antiarrhythmic Drugs
V-W
class
Drugs
Ion channel
Conduction
Velocity
Refractory
Period
Automaticity
Ia
Disopyramide
Procainamide
Quinidine
Na+
(intermediate)



Ib
Lidocaine
Mexiletine
Na+
(fast)
/


Ic
Flecainide
Propafenone
Na+
(slow)



II
Betablockers
Ca++ (indirect)



III
Amiodarone
Dofetilide
Dronedarone
Ibutilide
Sotalol
K+



http://www.cvpharmacology.com/antiarrhy/potassium-blockers.htm
Pharmacology of Antiarrhythmic Drugs
V-W
class
Drugs
Ion channel
Conduction
Velocity
Refractory
Period
Automaticity
Ia
Disopyramide
Procainamide
Quinidine
Na+
(intermediate)



Ib
Lidocaine
Mexiletine
Na+
(fast)
/


Ic
Flecainide
Propafenone
Na+
(slow)



II
Betablockers
Ca++ (indirect)



III
Amiodarone
Dofetilide
Dronedarone
Ibutilide
Sotalol
K+



IV
Diltiazem
Verapamil
Ca++



Drug
Bioavail
ability
(%)
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
Renal
Hepatic
6 – 10 hr
3A4
-
No
Dronedarone
4 – 15
Hepatic
13 – 19 hr
3A4
2D6, 3A4
Yes
Flecainide
90 - 95
Renal
Hepatic
10 – 20 hr
2D6, 1A2
2D6
No
Ibutilide
n/a
Hepatic
Renal
~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
Hepatic
Renal
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 iodine
Beta-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-blocker
CCB
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 betablocker
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 deficiencies
Low K+ and/or Mg++
Drug Interactions
•Diuretics
•Other QT prolonging
drugs
Examples of QTc Prolonging Drugs
Psychotropics
Anti-infectives
• Haloperidol
• Risperidone
• Ziprasidone
• Olanzapine
• Quetiapine
• Macrolide antibiotics
• Quinolone antibiotics
• Bactrim
• Azole antifungals
Antidepressants
Quinine
• SSRIs
• Tricyclic antidepressants
Methadone
Promethazine
Tacrolimus
http://www.crediblemeds.org/everyone/composite-list-all-qtdrugs/
Bauman JL. Eur Heart J 2001;3:K93-K100.
Common Antiarrhythmic Drug Interactions
Avoid/Contraindicated
Use caution
• QTc prolonging drugs
• Amiodarone, Dronedarone
• Amiodarone, Dronedarone
• Strong CYP3A4 inhibitors
• Dofetilide
• Verapamil
• Cimetidine
• Hydrochlorothiazide
• Trimethoprim
• Warfarin
• Statins
• Digoxin
• Propafenone
• Itraconazole
• Strong CYP2D6 inhibitors
• Ketoconazole
• Moderate CYP3A4 inhibitors
• Prochlorperazine • Flecainide
• Megestrol
• Moderate/strong CYP2D6
inhibitors
• Propafenone, Flecainide
• HIV protease inhibitors
Antiarrhythmic Drug Selection for Maintaining Normal Sinus Rhythm
No/Minimal
Structural
Heart Disease
Hypertension
Amiodarone
Dofetilide
Heart Failure
Substantial
LVH
≠ LVH
Dronedarone
Flecainide
Propafenone
Sotalol
Coronary Artery
Disease
Amiodarone
Dofetilide
Sotalol
Catheter
Ablation
Amiodarone
Dofetilide
Amiodarone
Dofetilide
Catheter
Ablation
Wann LS, et al. Circulation 2011;123:104-23.