Download 1100_Jacob Koruth - New Cardiovascular Horizons

Antiarrhythmic Agents
All you need to know
Jacob S Koruth, MD
Assistant Professor of Medicine
Director, Experimental Laboratory
Cardiac Arrhythmia Service
The Mount Sinai Hospital
New York , NY
Pharmacodynamics
• Ionic Channels – three states
– Resting, open, inactivated
– Drugs bind to channels preferentially in these states
– Have differing rates of binding and unbinding
• Use dependence- At ↑ HR: more pronounced
effect- Class I drugs
• Reverse use dependence- At ↓HR: potassium
channels ↑ active- therefore ↑ pronounced
effect- Class III drugs
Vaughn Williams Classification
• Simplistic- classifies drugs based on main
action
• Class 1- Sodium channel block- slow
conduction
• Class II- Beta blockers
• Class III- Potassium channel
• Class IV- Calcium channel blockers
Class 1
• 1a- Moderate Na block
– At rapid rates slow conduction, also block K
• 1b- Weak Na block
– Minimal block in resting tissue
– Marked block in activated tissue
– Dissociates rapidly- no use dependence
• 1c- Strong Na block
– Significant conduction slowing
– Increase QRS duration
– More effect at rapid rates- use dependent
Quinidine- Ia
• Na & K+ channel blockade – IKr , IKs, Ito
• Alpha receptor blocker
• Dose 600-1600 mg day BID or TID
Clinical use
• Refractory VT, often in combination with
mexilitine (after other AA drugs fail)
• Limited use for AF due to side effect profile
• Very difficult to find
VF prevention in patients with
Brugada or early repolarization
Procainamide- Ia
•
•
•
•
•
•
Na blocker
NAPA is K blocker
Minimal negative ionotropic effect
Only available IV in the US
Load 10-14 mg/kg given slowly
Maintenance 1-4 mg/min
Procainamide- Clinical utility
• Conversion of AF to NSR
• Slow rate and convert preexcited AF
• Unmask Brugada syndrome
Disopyramide - Ia
•
•
•
•
•
Na channel blockade
400 to 800 mg/day given BID
Potent Vagolytic/anticholinergic
Negatively ionotropic
Hepatic and renal excretion
Disopyramide - Side effects
• Anticholinergic
– Dry eyes, urinary retention, constipation
• Heart failure
• Torsades
• AF to rapid flutter (can enhance AV nodal
conduction)
Disopyramide - Summary
• Disopyramide:
– Vagal AF
– HOCM (with AF)
Lidocaine- Ib
• Na channel block- minimal effect on atrium
• Works most in depolarized tissues such as
during ischemia
• Only IV
• Large boluses increase CNS toxicity
Mexilitine- Ib
•
•
•
•
•
Na channel blockade
Metabolized by CYP2D6
Renal clearance
450 to 750 mg/day given TID
GI side effects
Clinical use: Lidocaine/Mexilitine
• Lidocaine– Ventricular tachycardia
• Peri MI
• Scar related
• Mexilitine
– Used in combination for refractory VT
Propafenone- Ic
• Na Channel block & Beta blocker
• Slow onset and offset kinetics- use
dependent
• Slows conduction in fast response tissue
• Dose 450-900 mg/day divided BID or TID
• Hepatic metabolism and renal clearance
Propafenone-Side effects
•
•
•
•
Proarrhythmia
Metallic taste
Constipation, nausea
Slight increase in pacing and defibrillation
thresholds
• Negative ionotrope
Flecainide- Ic
• Na blockade / IKr blockade
• In atrial tissue, prolongs action potential in
rapid rates: More active at faster rates
• Purkinje tissue APD shortened (Na)
• Ventricular tissue APD prolonged (K)
Flecainide- Ic
•
•
•
•
Dose 50 to 150 mg BID
Long half life
CYP2D6 metabolism and renal excretion
Renal excretion usually rapid even for slow
metabolizers
Flecainide-Side effects
• Proarrhythmia: Aflutter – 1:1 conduction
• Must prescribe AV nodal agents even if pt
has no h/o of flutter
• Renal insufficiency can lead to toxic levels
especially for slow metabolizers
Clinical use of Ic
•
•
•
•
Acute conversion of AF (60-70%)
Maintenance of NSR (30-40%)
Must be used with AV nodal blockers
Consider stress testing- if QRS increases
25% consider termination
Amiodarone
• Class III but multiple effects
• Prolongs APD and refractoriness in all
cardiac tissues
• Blocks all channels
Amiodarone
• Prolongs QT but Torsades uncommon
• Large volume of distribution– Long elimination half life 16-180 days
– 50% is eliminated within 3-10 days
Amiodarone-Side effects
•
•
•
•
•
•
IV - hypotension
Pulmonary fibrosis
Thyroid
Gastrointestinal- nausea, anorexia,
Hepatic- transient transaminitis common
discontinue if 3 x normal or 2x levels at baseline if abnormal
Ocular- keratopathy with corneal microdeposits in virtually all
patients, 10% with halo vision/dry eyes
Neurologic- 50%- peripheral neuropathy, paresthesia, malaise/fatigue,
tremors, dizziness, HA, sleep disorder
Photosensitivity- 15% - blue/gray tanning or burning
•
Bradycardia common
•
•
Thyroid Effects
• 37% iodine by weight
• 30% pts have early laboratory abnormalities
– T4 levels rise 20-40% in first month then return
to high normal
– T3 decreases by 30% in first few weeks then
returns to low normal
– TSH rises initially then returns to normal
• 5-10% clinical effects- either hypo or hyper
Pulmonary complications
•
•
•
•
•
1-17%
Rarely early- hypersensitivity pneumonitis
Most with late interstitial fibrosis
Reduced DLCO
Probably dose related but some paradoxical
with low dose
• Annual CXR and PFT recommended, but
efficacy not proven
Amiodarone- Clinical uses
• Conversion of AF
– 25-30% acute success
• Maintenance of NSR- highest of any AA
drug
– About 60% success at 1 year
• Ventricular tachycardia
• VF/polymorphic VT (ACLS)
Sotalol
• Ikr blocker + B blocker
• QT prolongation at higher doses and increases
linearly with dose
• Avoid if Cr clearance ≤ 40 ml/min
• 160 mg – 360 mg /day as BID dose
• Reverse use dependence
• ↓effective than amiodarone and ~Ic for AF
• Ventricular tachycardia: ischemic heart
disease, ARVC
Sotalol-Side effects
• B-blocker related
• CHF 3.3%
• Torsades 2.4% mostly in first week or after dose
change
– More common in
•
•
•
•
•
•
•
Women
High dose
CHF
Recent DCCV
Hypokalemia
Bradycardia
Renal insufficiency
Ibutilide
• Structurally similar to sotalol
• Only IV
• Watch QT interval
Dofetilide
• Pure IKr blocker
• Prolongs action potential, both atrial and
ventricular refractory periods
• QT interval with dose related prolongation
• Modestly reverse use dependent
Dofetilide
• Renally excreted- doing based on CrCl
• 20% degree of metabolism by CYP3A4inhibitors use with caution
• Half life of 10 hours
• Contraindicated with verapamil- results in 40%
increase in peak levels- also with drugs that
inhibit cationic renal secretion
• Uncorrected hypokalemia contraindicated
• Diuretics to be used with caution
Dofetilide
• Can only be prescribed by authorized users
• Initiation must be done as inpatient (3 days)
• Contraindicated if baseline QTc greater than
440 msec or 500 msec in presence of BBB,
delta wave, pacing
Clinical use
• 30% AF to NSR conversion rate
• 40-50% maintenance of NSR
• Safety in HF
– DIAMOND CHF
• 1518 patients with class III and IV CHF, EF<35%
• No difference in total mortality, cardiovascular
death, successful resuscitation
• 25 episodes of Torsades
Dronadarone
• Multiple channel blocker
• More Ikach blocking than amiodarone
• Extensive first pass metabolism- 15%
bioavailability
• Metabolized by CYP3A4
• Can see 10-15% creatinine rise, not true
decrease in GFR
• One dose 400 mg BID
Ivabradine
• If inhibitor
• Anti-anginal
• Inappropriate sinus tachycardia