ANTI-ARRHYTHMIC DRUGS Flashcards
How many phases are there in the cardiac action potential?
5 phases
Phase 0,1,2,3 and 4
What is the current flow in phase 0 of the action potential?
Phase 0 begins with fast inward sodium current that taken the membrane potential from resting (-85 mV) to above zero
What is current flow in phase 1 of the action potential?
In phase 1 there is an outward sodium current that causes the action potential to “dip” a little
What are the currents in phase 2 of the action potential?
Phase 2 is the plateau phase marked by a balance between an inward calcium and outward potassium current
What are the currents in phase 3 of the action potential?
In phase 3 there is an outward potassium current which leads to repolarization
What is phase 4 of the action potential?
Phase 4 in non-pacemaker cells is flat but in pacemaker cells there is slow depolarization due to funny sodium channels “If” channels
Surface electrocardiogram is a summation of which action potentials?
ECG is a summation of all the action potentials in the heart cells, i.e atrial mycocytes, SA/AV nodes, His Bundles, Purkinjie fibers and ventricular myocytes
Are all cardiac cell actions potentials the same?
No
Different cells have slightly different action potentials
Which classification is used for anti-arrhythmic drugs?
Vaughan Williams classification
What is Class I drugs in the Vaughan Williams classification?
These are sodium channel blockers
They slow the conduction velocty by blocking Na channels of phase 0
Class I drugs will prolong which interval on the ECG?
QRS interval
They will slow conduction velocity of phase 0 by blocking fast Na channels
What are the three states of the sodium channels?
Resting: Na channels are closed in this state and the membrane potential is at the resting potential
Activated: Na channels are open when the membrane potential reaches threshold potential causing a rapid influx on sodium ions
Inactivated: As the membrane potential depolarizes, Na channels close again in this state and remain closed till membrane potential is restored
What are the subclassification of Class I drugs?
Type 1A
Type 1B
Type 1C
Drugs in Type 1A?
Quinidine
Procainamide (IV)
Disopyramide
Effects of Type 1A drugs?
Block sodium channels
Also prolong action potential duration
Strong negative inotropes
Main uses of Class IA drug Quinidine?
Quinidine has a niche use in Brugada syndrome (ito blockade)
Side effects of Class IA drug Quinidine?
Diarrhea, torsades, thrombocytopenia/leukopenia, drug interactions, hypersensitivity
Main uses of Class IA drug Procainamide?
Pre-excited atrial fibrillation
Terminating monomorphic VT
Inducing Brugada ECG pattern (diagnostic purposes)
Unique metabolite of procainamide and it’s effects?
Procainamide is metabolized to NAPA (N-acetyl procainamide) by plasma acetylation and has Class III properties and can cause LQTS/Torsades
Side effects of Class IA drug Procainamide?
Lupus like syndrome
Torsades
Agranulocytosis
Main use of Class IA drug Disopyramide?
Niche use in HCM and vagally mediated atrial fibrillation
Side effects of Class IA drug Disopyramide?
Anticholinergic effects such as dry mouth, urinary retention and avoid in BPH and glaucoma
Strong negative inotrope effect and avoid in HFrEF
Type 1 B drugs?
Lidocaine (IV)
Mexiletine (PO)
Effects of Type 1B drugs?
Little effect on atrial tissue
Greatest effect on diseased ventricular myocytes
Main use of Class B drugs?
These are used in ventricular arrhythmias
Main use of Class IB drug Lidocaine (IV)
Terminate/prevent VT especially post MI
Torsades de pointes
Note: Not used prophylactically after MI
Main side effects of Class IB drug lidocaine?
Neurologic/CNS
Sinus node slowing
Increased risk in CHF and shock
Lower levels with hepatic enzyme inducers (phenytoin, rifampin, barbituates)
Main uses of Class IB drug Mexilitine (oral)?
Niche use in ICD shocks
congential LQT3
Main excretion/clearence of Class IB drug mexilitine?
Hepatic clearence (90%)
Main side effects of Class IB drug mexilitine?
Neurologic/CNS and GI symptoms
Type 1 C drugs?
Flecanide
Propafenone
Effects of Type 1 C drugs?
Most potent Na blocking drugs (Can prolong QRS on ECG)
Negative inotropes
Main use of Class IC drugs?
Atrial arrhythmias
Idiopathic VT
Class IC drugs are contraindicated in?
CAD
HFrEF
These are strong negative inotropes
Main uses of Class IC drug Flecanide?
Atrial fibrillation
SVT
WPW syndrome
Idiopathic VT
What did flecanide show in the CAST (Cardiac arrhythmia suppression) trial?
Flecanide use doubled mortality after MI including VT and should not be used in MI.
Don’t use in patients with structural heart disease
Unique side effect of flecanide and how to treat it?
Flecanide can cause afib to change to atrial flutter with 1:1 conduction. Give with a beta-blocker or calcium channel blocker
Use dependence of flecanide?
At higher heart rates, flecanide’s effects increase and can cause rate dependent AV block
Side effects of Flecanide?
Parasthesias
Diplopia
Chest pain
Main uses of Propafenone?
Atrial fibrillation
SVT
Propafenone is contraindicated in?
MI & structural heart disease
Note: It wasn’t used in the CAST trial but results apply to it as it is similar to flecanide.
Unique effect of Propafenone?
Propafenone has some intrinsic beta blocker activity
What is Class II drugs in the Vaughan Williams classification?
These are Beta-adrenergic blockers
Examples of drugs in Class II?
Metoprolol
Atenalol
Propranolol
Carvedilol
Esmolol
Mechanism of action of Class II drugs?
They decrease cytosolic calcium
Effects of Class II drugs?
Slow sinus rate
Prolong AV conduction and refractoriness
Inhibit automaticity
Block cardiac sympathetic innervation and effects of circulating catecholamines
Class II drugs effects of ECG?
Increase P-P interval (SA Node)
Increase PR interval (AV node)
Main use of Class II drugs?
Beta-blockers are useful in:
Mortality benefit and anti-arrhythmic effect post MI and chronic CHF
Control of ventricular rate in atrial fibrillation
Useful in VT storm (without cardiogenic shock)
Use of Class II beta-blockers in torsades?
Beta-blockers are useful in preventing torsades in patients with congenital LQTS but not drug induced LQTS (these are bradycardia dependent)
Main side effects of Class II drugs?
Bradycardia
Hypotension
What is Class III drugs in the Vaughan Williams classification?
These are Potassium channel blockers
Drugs in Class III?
Sotalol
Dofelitide
Ibutilide
Amiodarone
Dronedarone
Why are amiodarone and dronedarone unique drugs?
They have properties of all 4 Classes!
Effects of Class III drugs?
They block potassium channels and therefore outward potassium current (phase 3) causing slowing of repolarization and increase in action potential duration.
ECG effect of Class III drugs?
They will prolong the QT interval
Main uses of Class III drug Sotalol?
Atrial fibrillation
Ventricular tachycardia in patients with ICDs
Unique effect of Sotalol?
Sotalol has mild beta blocker effect Class II
Side effects of Class III drug Sotalol?
Major risk is LQTS/Torsades due to reverse use dependence
May lower DFT
Excretion of Sotalol?
Mostly renal
Main uses of Class III drug Dofelitide?
Persistent atrial fibrillation
(on the basis of the DIAMOND studies)
Side effects of Class III drug Dofelitide?
LQTS/Torsades
May lower DFT
Excretion of Class III drug Dofelitide?
Renal
Main use of Class III drug Ibutilide?
Atrial fibrillation
Atrial flutter
Note: Converts 30-60% of afib and flutter. Conversion better for flutter than fibrillation. Can facilitate DCCV of afib
How is Class III drug Ibutilide administered?
1 mg given over 10 minutes and may repeat x 1
Side effect of Class III drug Ibutilide?
Risk of LQTS/Torsades
(Maybe reduced with magnesium pre-treatment)
Main use of Class III drug Amiodarone?
Most effective for recurrent AF
Most effective for VT/VF causing ICD shocks
Occasionally used for SVTs
Side effects of Class III drug Amiodarone?
May raise DFT slightly
Cardiac: AV block, bradycardia, LQTS/torsades
Pulmonary: Fibrosis, bronchiolitis obliterans
Thyroid: Hypo>Hpyer
Gastrointestinal: Hepatitis, transaminitis, nausea
Neurologic: Ataxia, tremor, neuropathy
Ocular: Corneal deposits, retinopathy
Skin: Photosensitivity, blue skin
Unique effect of Amiodarone?
Has all Class effects I-IV
Main uses of Class III drug Dronedarone?
Approved for AF/Flutter only
Class III drug Dronedarone is not indicated in?
VT or VF
Class III drug Dronedarone is contraindicated for?
Systolic heart failuire (ANDROMEDA trial)
Permanent AF (PALLAS trial)
What is Class IV drugs in the Vaughan Williams classification?
These are the calcium channel blockers
Drugs in class IV?
Verapamil and Diltiazem
Mechanism of action of Class IV drugs?
Block L type calcium channels causing decrease in cytosolic calcium
Effects of Class IV drugs?
Prolong AV node conduction and refractoriness
Mild effect on SA node
Main use of Class IV Calcium channel blockers?
Greatest effect on AV node > Sinus node
Rate control of AF
Termination and chronic suppression of PSVT
Note: IV verapamil as effective as adenosine for PSVT
Side effects of Class IV calcium channel blockers?
Hypotension, constipation, peripheral edema, negative inotropy (don’t use in systolic HF)
May raise digoxin levels
Synergistic bradycardic effects with beta-blockers
What is the concept of use dependence?
Greater drug effect at faster HR
Which drugs show use dependence and whats the benefit and drawback?
Type 1C drugs such as flecanide and proafenone
We want them to work more when there is a tachyardia so thats the benefit
Negative is that they can cause rate dependent AV block by being too efecacious
What is the concept of reverse use dependence?
Greater drug effect at slower heart rates
Which drugs show reverse use dependence and what is the drawback?
Type III drugs such as dofelitide and sotalol
At slower heart rates they can cause prolonged QT and precipitate LQT/Torsades
Major pro-arrhythmic effects of Class I drugs?
Rate dependent AV block (type 1c)
Promote monomorphic VT in patients with cardiomyopathy
Major pro-arrhythmic effects of Class III drugs?
Brady-dependent LQTS/Torsades
What causes QT prolongation?
Results from prolongation of action potential duration
Which drug classes can prolong QT?
Class 1A drugs
Class III drugs
What other factors can cause QT prolongation?
Low Mg, Low K
Using drugs that prolong QT
(Chloroquine, chlorpromazine, droperidol, erythromycin, haloperdol, methadone, pentamidine, moxifloxacin)
Using drugs that inhibit metabolism of AADs
What is Torsades de pointes?
Tdp is a polymorphic VT that occurs in the setting of a long QT interval.
Usually we have a baseline normal sinus rhythm with a prolonged QT and PVCs where a PVC can trigger polymorphic VT which then degenerates to v-fib
Treatment of torsades de pointes
Withdraw offending agent
Magnesium IV
Correct hypokalemia
Isoproterenol or pacing at 90-100 bpm to reduce QT interval
IV lidocaine
Don’t use amiodarone or procainamide as they can prolong QT
No beta blockers due to reverse use dependence
If degenerates to v-fib then defibrillate
Which AADs increase ICD defibrillation thresholds and pacing thresholds?
Sodium channel blockers
Mexilitine
Flecanide/propafenone
Amiodarone (has all 4 class properties)
Which AADs decrease ICD defibrillation thresholds and pacing thresholds?
Potassium channel blockers such as sotalol and dofelitide
Which AADs can bring out a latent Brugada pattern?
Type 1 AADs
Note: Here we see Type 1 pattern come out after 15 minutes of Type 1 AAD. Initially we have a Type III pattern
Can be used as a diagnostic tool
What is a unique effect of Type Ic drugs on atrial fibrillation?
Type 1C drugs, especially flecanide can cause atrial fibrillation to organize to slow atrial flutter with 1-1 AV conduction
How can we prevent the risk of atrial fibrillation slowing to atrial flutter with 1:1 conduction with Type 1c drugs?
Give beta-blockers or calcium channel blockers with Type 1c drugs such as flecanide
What are some pro-arrhythmic effects of digoxin?
Atrial tachycardia or atrial fibrillation with 2nd or 3rd degree AV block
Bidirectional VT
Ventricular fibrillation
Which AADs are excreted renally?
Sotalol
Dofelitide
Digoxin
Note: Reduce dose in CKD
Which drugs are excreted by liver?
Lidocaine
Propafenone
Amiodarone
Reduce dose or avoid in liver disease
AAD drug elimination
What is the interaction between amidarone and Warfarin?
Amiodarone inhibits CYP 2C9 and leads to higher levels of Warfarin
What is the interaction between Verapamil and Droedarone?
Verapamil inhibits CYP3A4 and can increase dronaderone levels
CYP drug interactions?
What is the P-glycoprotein pathyway?
This is an excretion pathway where drugs are attached to the P glycoprotein which transports drugs and is found in GI tract, liver and kidney
What is the P-glycoprotein pathyway?
This is an excretion pathway where drugs are attached to the P glycoprotein which transports drugs and is found in GI tract, liver and kidney
What are the substrates for the P-glycoprotein pathway?
Digoxin
Dabigatran
Anti-neoplastic drugs
What are inducers of P glycoprotein pathway?
Rifampin
HIV protease inhibitors
Note: These drugs will decrease levels of substrates (digoxin and dabigatran)
What are the inhibitors of the P glycoprotein pathway?
Amiodarone
Dronedarone
Verapamil
Quinidine
Erythromycin
Ketoconazole
Itraconazole
Cyclosporine
Note: They will increase the levels of the substrates (digoxin, dabigatran)
Main uses of digoxin?
Major use is in atrial fibrillation with concurrent CHF
Also useful if BB or CCB inadequate
Digoxin not useful for which atrial fibrillation?
Paroxysmal atrial fibrillation as it does not prevent paroxysms or terminate AF
Mechanism of actions for digoxin?
Mechanism 1: Blocks NA-K ATPase and increases intracellular Ca increasing contractility
Mechanism 2: Increase vagal tone
Main side effects of digoxin?
Nausea, vomiting
Visual disturbances
CNS
Proarrrhythmias : AT or AF with AV block, bidirectional VT, VF
Treatment for Proarrrhythmias caused by digoxin?
Correct K/Mg
Atropine/pacing for bradycardia
Lidocaine for VT/VF
Anti-digoxin Fab antibody fragments (digiband) for refractory VT/VF, hyperkalemia
Excretion of Digoxin is via this pathway?
P-glycoprotein transporter and excreted via kidneys
Half-life of digoxin?
1.5 to 3 days
What did the DIG trial show?
DIG trial was a RCT of 6800 patients with CHF, LVEF <45% who were on digoxin. There was no benefit in mortality.
A secondary analysis showed that there was an increase in mortality with higher digoxin levels >1.1 and serum levels <0.8 were associated with a lower mortality. Therefore, minimize digoxin use but if used keep levels less than or equal to 0.8
Which drugs increase digoxin levels?
Levels increase with amiodarone, dronedarone, verapamil
Mechanism of action of nucleoside adenosine?
Binds to adenosine A1 receptor and activated outward potassium current in the atrium. Also has CCB effect
Main uses of Adenosine?
Terminate SVT (AVNRT, AVRT, AT)
How is adenosine administered?
Give adenosine 6 mg rapid IV push. If no conversion give 12 mg IV push and can repeat 12 mg dose once more
Note: Try vagal maneuvers first
Half life of adenosine?
10 seconds
Side effects of adenosine?
Flushing, headache, chest pain
Asystole
Atrial fibrillation (10-15%)
Bronchospasm (avoid in asthmatics)
What blunts adenosine effects?
Caffeine
Theophylline
What enhances adenosine effects?
Dipyridamole
Heart transplant
Mechanism of action of Ranolazine?
Blocks late sodium current and shortens APD
Main use of Ranolazine?
FDA approved for chronic stable angina
Also reduced NSVT, SVT, and AF in MERLIN-TIMI-36 trial
Ranolazine use for VT/VF?
RAID trial in ICD pateints showed ranolzine reduced recurrent VT/VF ICD therapy for treated VT or VF . It did not reduce the primary end point of first treated VT/VF or death.
Prevention of VT/VF
What did the cardiac arrhythmia suppression trial show (CAST)?
This was a trial done in patients that were post MI and frequently had reduced EF with PVCs/NSVT and used Class Ic agents like encainide and flecanide. These drugs suppressed PVCs/NSVT BUT
Doubled mortality and could cause VT as well. Therefore, they carry a black box warning and shouldnt be used in patients with MI (and structural heart disease such as low EF).
Prevention of VT/VF
Effect of Sotalol on mortality for treatment of VT/VF?
Use of sotalol increased mortality when used for VT/VF (SWORD trial Lancet 1996)
Prevention of VT/VF
Effect of Dofelitide on mortality for treatment of VT/VF?
Neutral (DIAMOND-MI Trial Lancet 2000)
Prevention of VT/VF
Effect of Dronedarone on mortality for treatment of VT/VF?
Mortality increased (ANDROMEDA NEJM 2008). In Andromeda trial patients had heart failure with reduced ejection fraction. Therefore, dronaderone should not be used in these patients, it is contraindicated
Prevention of VT/VF
Effect of Amiodarone on mortality for treatment for VT/VF?
Mixed study results but no proven benefit on moratlity
Prevention of VT/VF
What was the SCD-HeFT trial?
This was a study of about 2500 subjects with LVEF <35% and NYHA II-III symptoms who were randomized to receive amiodarone, placebo or ICD therapy and followed for 48 months
Prevention of VT/VF
What did the SCD-HeFT trial show?
There was no benefit to amiodarone over placebo. However, ICD showed significant reduction in mortality
Treatment of VT/VF arrest
First step in treatment of pulseless VT/VF arrest?
Shock
Treatment of VT/VF arrest
If pulseless VT or VF arrest refractory to initial shock?
Give amiodarone 300 mg IV/IO and can repeat boluses of 150 IV/IO
Note: Lidocaine can be used as an alternative
Treatment of VT/VF arrest
What did the ARREST trial show?
ARREST trial analyzed 504 patients with out of hospital cardiac arrest refractory to initial shock and use of amiodarone improved % patients surviving to admission
Treatment of VT/VF arrest
What did the ALIVE trial show?
AlIVE TRIAL analyzed 347 out of hospital cardiac arrest patients refractory to initial shock treat with amiodarone vs lidocaine and showed amiodarone more effacacious than lidocaine.
Treatment of sustained monomorphic VT (with a pulse)
If patients are relatively stable then IV amiodarone 150 mg IV over 10 minutes and repeat as needed.
Procainamide IV if no severe CHF or MI. 20-50 mg/min until hypotension or QRS duration increased by 50%
Lidocaine can be used but is less effective than procainamide
Beta-blockers/verapamil can be used for idiopathic VT
Prevention of ICD shocks
Which AAD is most effective for preventing ICD shocks?
Amiodarone is the most effective
Note: Based on the OPTIC trial that compared beta-blocker to sotalol and amiodarone + beta blocker
Prevention of ICD shocks
Order of efficacy of AADs in prevention of ICD shocks?
Amiodarone > Sotalol > beta-blocker alone
Prevention of ICD shocks?
Second line agent is first line agents are not working?
Mexilitine
Prevention of ICD shocks
When should cathetar ablation be used?
For treatment of monomorphic VT
Prevention of ICD shocks?
First use amiodarone + beta-blocker
Sotalol can be used as well
Mexilitine as second line
Cathetar ablation for monomorphic VT
First line treatment of acute termination of regular SVT?
Vagal maneuvers or IV adenosine
If Vagal maneuvers or IV adenosine don’t work for acute termination of regular SVT and patient is hemodynamically stable?
IV beta blockers
IV Diltiazem or Verapamil
If these fail then cardiovert (synchronized)
If Vagal maneuvers or IV adenosine don’t work for acute termination of regular SVT and patient is hemodynamically unstable?
Synchronized cardioversion
First line treatment for chronic SVT?
Ablation
Chronic medical therapy if ablation refused or contraindicated?
Beta-blockers, Diltiazem, Verapamil (note: if no pre-excitation)
Other therapies for chronic medical therapy for SVT?
Flecanide. Propafenone (Class IIa)
Amiodarone, Sotalol, Dofelitide (Class IIb)
Which drugs can be utilized for acute termination of atrial fibrillation?
Class I: Flecanide, propafenone, dofelitide, IV ibutilide
Class IIa: Oral amiodarone
Anticoagulation consideration when using AAD for atrial fibrillation?
Patients should be anticoagulated three weeks prior and 4 weeks post conversion to normal sinus rhythm (same as DCCV)
Pill in pocket approach for acute termination of atrial fibrillation?
Class IIa recommendation is to use propafenone or flecanide preferrably with a beta blocker to prevent Aflutter with 1:1 conduction. First dose should be initiated under observation
Which AADs can be used for maintenance of sinus rhythm in atrial fibrillation patients with no structural heart disease (no CAD, LVH or HFrEF)?
All of them
First line: Dofelitide, Dronaderone, Flecanide, Propafenone, Sotalol
Second line: Amiodarone
Note: Cathetar ablation can also be offered
Which AADs can be used for maintenance of sinus rhythm in atrial fibrillation patients with LVH > 1.5 cm?
Dronaderone is first line
Amiodarone second line
Which AADs can be used for maintenance of sinus rhythm in atrial fibrillation patients with CAD?
First line: Dofelitide, Dronaderone, Sotalol
Second line: Amiodarone
Note: Cathetar ablation can be offered as well
Which AADs can be used for maintenance of sinus rhythm in atrial fibrillation patients with heart failure with reduced ejection fraction?
First line: Amiodarone and Dofelitide
Cathetar ablation can be offered as well
What did the Canadian trial of Atrial fibrillation (CTAF) show in terms of maintanence of NSR?
Amiodarone most effective when compared to propafenone or sotalol (60% vs 30%)
What did the SAFE-T trial show in terms of maintence of sinus rhythm in atrial fibrillation?
This trial showed amiodarone was superior to Sotalol
What did the DIONYSOS trial show in terms of maintence of sinus rhythm in atrial fibrillation?
Amiodarone was superior to Dronaderone
Drug of choice in pre-excited atrial fibrillation in patients that are hemodynamically stable?
First line: Procainamide and Ibutilide
Avoid beta-blockers, CCBs, adenosine, digoxin and amiodarone as they can degenerate it to VF
Note: If patient is hemodynamically unstable then DCCV
Which AADs are safe in pregnancy to use?
Adenosine
Metoprolol
Digoxin
Lidocaine
Propranalol
These drugs should be avoided in pregnancy?
Amiodarone
Atenalol
Dronaderone
AADs in prevention of SCD due to VT/VF?
No value of AADs for prevention of SCD (except beta-blockers)
Drugs of choice in VF/pulseless VT arrest?
Amiodarone or Lidocaine
Drugs of choice for termination of monomorphic VT with a pulse?
Amiodarone or Procainamide
Drugs of choice for prevention of ICD shocks?
Amiodarone > Sotalol
Second line: Mexilatine
