1. Antiarrhythmic Medications
My name is Tim Humlicek, and I’m currently the heart failure and heart transplant pharmacist at Texas Children’s Hospital.
Today I plan to talk about Antiarrhythmic medications, but before we get to treatment
We should talk about normal rhythms in normal hearts
The heart normally beats with a regular rhythm,
in adults, this is around times per minutes
and in children a normal heart rate varies based on age
Each beat originates with depolarization of the sinus node and
The usual every day cardiac rhythm is called normal sinus rhythm
The term arrhythmia (or more accurately, dysrhythmia) is a disturbance in the rate, regularity, site of origin, or conduction of cardiac electrical impulse
A arrhythmia can be a single aberrant beat, or even a prolonged pause between beats, or a sustained rhythm disturbance that can persist a lifetime
Some arrhythmias are harmless, but others, however, can be dangerous and require immediate therapy to prevent sudden death
So today we will be talking about the medications used when there is a disturbance in rate, regularity, site of origin, or conduction of cardiac electrical impulse
Tim Humlicek, PharmD, BCPS
Texas Children’s Hospital

2. Objectives
Understand the underlying theory for the use of antiarrhythmic medications
Understand the mechanism of action for commonly used antiarrhythmic medications used in pediatric cardiac intensive care
Recommend a plan to monitor patients on antiarrhythmic medications
CHD defects occur in roughly 0.8% of live births, and roughly 30-50% will require at least 1 surgical corrections.
While arrhythmias vary based on anatomic defect.
When you think that electric physiology is a complex interplay between
Cardiac anatomy, chamber enlargement from abnormal pressure and volume loads, cellular injury from hypoxia and cardiopulmonary bypass, fibrosis at sites of suture lines and patches, and direct trauma to the specialized conduction tissues
It’s hard to imagine a more likely population for arrhythmias to occur than children with CHD
So by the end of today we will
Understand the underlying theory for the use of antiarrhythmic medications
Understand the mechanism of action for commonly used antiarrhythmic medications used in pediatric cardiac intensive care
Recommend a plan to monitor patients on antiarrhythmic medications

3. Now we’ve already learned about the origin of normal sinus rhythm in the sinoatrial node,
The SA node is the origin of the typical coordinated heartbeat, since the intrinsic firing rate is the fastest amongst all the cardiac electrical tissue.
Cells outside of the SA node in the atria typically fire more slowly
and the slowest in the ventricles
From the SA node the electrical activity travels throughout the intermodal tracts of the atria, telling the atria to contract to pump blood in to ventricles,
To allow adequate filling of the ventricles
The electrical signal take a detour in the AV node > His bundle > bundle branches > pukinje cells
And eventually down the bundle branches to the the apex of the heart
allowing the ventricles to eject deoxygenated blood into the pulmonary artery and oxygenated blood through the aorta in the normal four chambered heart

4. Types of Arrhythmias Arrhythmias of sinus origin Conduction blocks
Sinus Tachycardia, Sinus Bradycardia, Sinus Arrest, Asystole
Conduction blocks
AV Blocks (First Degree; Second Degree: Wenckebach, Mobitz Type 2; Third Degree; Bundle Branch Blocks; Hemiblocks)
Ectopic rhythms
Supraventricular & ventricular arrhythmias
Pre-excitation
Wolff-Parkinson-White Syndrome, Lown-Ganong-Levine Syndrome
When there is a disturbance in this nicely coordinated mechanism, this is called an arrhythmia
There are 4 basic types of arrhythmias:
Electrical activity follows the usual conduction pathway, but are otherwise too fast, too slow, or irregular (arrhythmias of sinus origin)
Some examples are sinus tachycardia, sinus bradycardia, sinus arrest, and asystole
2. Electrical activity originates appropriately but encounters blocks or delays (conduction blocks)
Some examples are AV blocks (first, second, and third), bundle blocks, and hemiblocks
3. Electrical activity originates elsewhere than the sinus node (known as ectopic rhythms)
If other potential pacemakers in the heart can be stimulated to depolarize faster and faster until they can overdrive the normal sinus mechanism and establish their own transient or sustain rhythm
4. The last basic type are pre-excitation arrhythmias where
There is an accessory pathway that bypass the normal pathway, providing a short circuit (preexcitation)
The latter two types will be the focus of our presentation today

5. Supraventricular Tachycardia (SVT)
Abnormally high heart rate originating above the Bundle of His
Narrow QRS complex
Can be re-entrant or focal (i.e. ectopic focus)
Re-entrant ~90% of SVT
Can be incessant or paroxysmal (burst from seconds to minutes)
Morbidity:
Heart failure
Other arrhythmias
Arrhythmias happen due to a number of factors including:
hypoxia, ischemia, sympathetic stimulation (hyperthyroidism, CHF, nervousness, exercise), drugs, electrolyte disturbances, bradycardia, and stretch
One of the more common arrhythmias that we observe in pediatric cardiology that can require pharmacotherapy is
supraventricular tachycardia, which is an umbrella term for several more specific types
SVT refers to the likely origin of the dysrhythmia; above the Bundle of His
The risk of any type of SVT is thought to be within 21-28% of children with CHD
There are several distinct types of SVT, which we will go over in a second, but they often share some common characteristics
They typically have a narrow QRS complex (<0.12 seconds in duration) indicating that conduction is proceeding through the most efficient route through the ventricles and indicates that the rhythm originates at or above the AV node. Unless there is a concominant block within the bundle branches.
The can be reentrant or have an ectopic focus, but most dysrhythmias of this types are re-entrant in nature
they can be incessant or paroxysmal (last seconds to minutes)
When the arrhythmias are intermittent, this tenders the observation that the symptoms often appear for short durations
They can also disappear as a child increases in age, but can reappear later on
They can cause significant morbidity if uncontrolled
Resulting in heart failure or generation of other arrhythmias

6. Re-entrant Tachycardia (AVNRT)
Re-entrant arrhythmia
AV Node
Common type of SVT
Age > 2 years
Morbidity
Palpitations, chest pain
Heart failure
AV nodal reentry tachycardia (AVNRT) is one common type of reentrant supraventricular tachycardia (SVT)
The cause for AVNRT is the presence of dual AV nodal pathways. Which we can observe in the picture on the right
In this dysrhythmia, a fast and a slow pathway of conduction are competing within the AV node
Typically the fast pathway is dominating since retrograde transmission from the slow pathway stimulus usually hits the cells of the fast pathway when they are in a repolarization phase (and therefore cannot conduct).
However, a premature atrial beat may cause an extra conduction down the slow pathway, and then retrograde up the fast pathway, resulting in a reentrant circuit
It can commonly occur in adolescents
AVNRT is typically well tolerated, but can sometimes result in hemodynamic compromise and heart failure

7. Re-entrant Tachycardia (AVRT)
Re-entrant arrhythmia
Orthodromic
Antidromic
Most common type of SVT
Neonates and infants
Morbidity
Other arrhythmias
Heart failure
AV reentrant tachycardia (AVRT) is another type of reentrant SVT common in neonates and infants < 2 years of age
As opposed to originating in the AV node like AVNRT,
AVRT occurs when a reentrant circuit is present outside of the AV node through an abnormal conduction pathway that connects the atrium to the ventricles.
This pathway is termed an "accessory pathway" or a "bypass tract".
Patients can present with palpitations or with impaired LVEF
The two main types are orthodromic (left in the cartoon above) and antidromic (which is on the right)
Orthodromics AVRT originates by atrial or ventricular beats
Antegrade conduction still occurrs via the AV node, but comes back with retrograde conduction via the accessory pathway when the atria and AV node are no longer in a refractory period resulting in tachycardia
To stop the retrograde conduction from producing further stimulus
These patients responds to therapies that lengthen AV nodal refractory period and depress its conduction
such as vagal maneuvers, adenosine, and calcium channel antagonists in hemodynamically stable patients
Other options like procainamide, beta antagonists can be used as well.
Antidromic AVRT, antegrade conduction occurs via the accessory pathway, with retrograde conduction through the AV node.
In this instance, AV nodal specific therapies like adenosine, beta blockers, and calcium channel blockers should be avoided until its definitively known to be antidromic AVRT and should be known as an undiagnosed wide QRS complex tachycardia.
Concerning is the possibility of starting these agents and allowing a faster accessory pathway and other foci to conduct unchallenged possibly resulting in ventricular fibrillation
For these patients, the typical drug used is procainamide

8. Atrial Tachycardia Atrial ectopic focus/foci Incessant SVT Morbidity:
“wandering pacemaker”
Incessant SVT
Approximately 10% of all SVTs
Adenosine can be diagnostic
Treatment challenges
<3 Years old
Morbidity:
Tachycardia induced cardiomyopathy
Heart Failure
Other arrhythmias
Atrial Tachycardia: Typically either atrial ectopic or focal atrial tachycardia
In lieu of a re-entrant mechanism. Another group of SVT includes atrial tachycardia
Resulting from the random firing of single atrial ectopic focus leading to a similar heart rate when the arrhythmias is occuring
Or sometimes multiple foci can contribute
When ventricular rate shifts between the Atria Focus/Foci and the SA node (based on increases/decreases vagal tone), this is known as a “wandering atrial pacemaker”
It is the most common cause of incessant SVT in children and accounts for 10% of all SVT
Although the arrhythmia itself may be sporadic
The endpoint is irregular ventricular rate, PR interval variation, and P-wave variability
It can eventually result in heart failure and other arrhythmias
vagal maneuvers typically have no effect and other treatment generally are not very effective since vagal tone is probably already increased
Although children with < 3 years old are better responders, the choice of drugs can be challenging as there are potentially several options
But digoxin with or without propafenone with or without amiodarone can work
However, only digoxin and amiodarone may have less negative inotropic effects, which is a concern in patients with depressed heart function
Older children who are less likely to respond may need to be considered for non-pharmacological treatment like ablation

9. Wolff-Parkinson-White
Re-entrant arrhythmia
ECG evidence of ventricular pre-excitation, slurred QRS upstroke (delta wave), short PR interval, wide QRS complex.
Also known as ‘pre-excitation’
The ventricles become polarized before conduction in the primary pathway occurs
Children with congenital heart disease
Ebstein’s anomaly
Morbidity:
Heart Failure
Other arrhythmias
Use of digoxin is contraindicated
WPW syndrome is a syndrome with a patient who has a symptomatic arrhythmias involving an accessory pathway that connects the atria and ventricles
In pediatrics, Ebstein’s anomaly and L-TGA patients (due to an Ebstein’s like malformation of the AV valve) are risk factors and can occur in up to 20% of patients.
Much like AVRT, this usually involves a reentrant mechanism
This accessory bundle is often a perfect substrate for reentry
The bundle of kent for example can also be a focus of preexcitation that is contributing to ventricular depolarization in usually one or more areas
Anterograde conduction via the accessory pathway results in earlier activation of part of the ventricles and some yet still by the faster route via the purkinje fibers (thus a wide QRS complex)
This results in a fusion beat since both systems of conduction are performing
due to the abberant signal conduction and depolarization of the ventricles of different parts of the ventricle simultaneously rather than a temporally defined order
There is also a shortened PR interval that is also characteristic (since the part of the ventricles are depolarizing sooner)
mild palpitations to syncope and, rarely, even sudden cardiac death, are the result of tachycardia,
Digoxin and calcium channel antagonists are considered to be contraindicated due to probably enhance anterograde conduction via the accessory since refractory period in the AV node will increase

10. Pharmacotherapy of SVT
Incessant (i.e. hemodynamic compromise)
Vagal maneuvers (i.e. ice to face)
Adenosine  β-antagonists (ie propranolol)
Paroxysmal
Beta-blockers (i.e. propranolol)
Second line:
Amiodarone, procainamide, sotalol, & flecainide
Use agent with fewest potential adverse events
As we have somewhat discussed, there are several options to treat SVTs
In the case of incessant and hemodynamically compromising SVT
Vagal maneuvers (like applying ICE to the child’s face without obstructing ventilation or blowing on an occluding straw) can work in some instances
While coordinating possible cardioversion or pharmacologic therapy if necessary
Pharmacotherapeutic options like adenosine and beta blockers can be used to break the rhythm until as other causes are resolved.
The most commonly used beta blockers to treat a dysrhythm are propranolol and metoprolol due to their widespread availability and liquid formulations for children
Other options include sotalol, flecainide, procainamide, and amiodarone

11. Junctional Ectopic Tachycardia
Primarily a post-operative arrhythmia
Ectopic focus at the His/Purkinje junction
Increased heart rate  decreased cardiac output
Stimulated by catecholamine release
Self-limiting
Typically resolves within 72 hours after surgery
Pharmacotherapy
Sedation and analgesia
Amiodarone
Limit patient movement
Neuromuscular blockade, lower body temperature
Risk factors for JET in children are surgeries taking place near the AV node (VSD closure or RV outflow tract repairs)
With a long bypass time, younger age, and inotropic medications, and hypomagnesemia
So there is an ectopic focus near the AV node
Firing around 170 – 260 beats per minute
Impulses conducted to atria and ventricle at the same time or they can be disassociated
JET is typically self limiting, but cannot be predicted when it will resolve.
Those with decreased cardiac output and hemodynamic instability should be treated and avoiding exogenous stimulus of catecholamines or using synthetic catecholamines can be detrimental.
Anxiolysis and sedation are important. Therefore, dexmedetomidine may play an important role here.
Milrinone, due to independence from Beta receptors, is the inotrope of choice
Amiodarone is also useful and has good efficacy to restore sinus rhythm 80-90% of the time

12. Atrial Fibrillation / Atrial Flutter
Re-entrant arrhythmia
Atrial flutter: single
Atrial fibrillation: multiple
Rare in neonates / infants
More common in older patients
Fontan procedure (may also include IART / ‘Scar Flutter’)
Pharmacotherapy
Limited, as most patients respond to cardioversion
β-antagonists if patients do not respond to cardioversion
In Atrial Flutter, a single constant reentrant circuit is responsible for the regular sawtooth pattern on the EKG
In atrial fibrillation there are multiple reentrant circuits are firing completely unpredictably so no true P waves can be seen.
The AV node is getting blitzed and allows only occasional impulses to pass through at variable intervals
Atrial Tachycardias like Afib and Aflutter are particularly rare in children
But can develop in any type of CHD lesion due to atrial scars from surgery and right atrial enlargement
Flutter is particularly problematic for patients with Fontan physiology (up to 50% in those who underwent older variations of the surgery– atriopulmonary connections) and in D-TGA patients who underwent Senning or Mustard procedures
If pharmacotherapy is needed, typically drugs are used for ventricular rate control, acute conversion, chronic suppression, as well as prevention of thromboembolism
Almost every class of antiarrhythmics have been attempted, but beta antagonists are useful here

13. Antiarrhythmic Mechanism(s)
Automaticity
Pacemaker cells
SA / AV node, ectopic sites
Decrease automaticity – decrease heart rate
Refractory Period
Time to recharge
Increase refractory period – decrease heart rate
Conduction Velocity
Speed of impulse
Decrease conduction velocity – decrease heart rate
Three mechanisms are the target of pharmacotherapy
Automaticity refers to the heart’s ability to spontaneously produce an action potential
Increase Phase 4 slope (rate of depolarization faster): stretch, beta agonism, hypokalemia, ischemia
Which in arrhythmias, your drug treatment will work on the SA/AV node, or an ectopic site
Refractory period refers to the time of repolarization that a cell needs before being capable of transmitting another signal
When you use a drug to prolong the refractor period, you will also end up decreasing the heart rate
Conduction velocity is the speed of impulse
Slowing this down also decreases heart rate

14. Vaughn-Williams Classification
Sodium Channel Antagonists (depress phase 0)
Subtypes: 1a, 1b, 1c
Class II
Beta-blockers (decreases slope of phase 4)
Class III
Potassium Channel Antagonists (prolongs phase 3)
Class IV
Calcium Channel Antagonists (prolong phase 2)
Digoxin
Adenosine
Class I
Sodium Channel Antagonists (depress phase 0)
Subtypes: 1a (moderate) , 1b (weak), 1c (strong)
Class II
Beta-blockers (decreases slope of phase 4)
Block sympathetic activity, reduce rate and conduction within heart electrical cells (SA node and AV Node) (bottom figure)
Class III
Potassium Channel Antagonists (prolongs phase 3)
Delay repolarization and increase action potential duration and effective refractory period
Class IV
Calcium Channel Antagonists (prolong phase 2)
Bock L-type calcium channels within the SA and AV node; reduce rate and conduction

15. Class I (Sodium Channel)
Procainamide
Mechanism: Class Ia (moderate blockade)
Dosing: I.V.: LD 3-6 mg/kg (maximum 100mg), followed by infusion mcg/kg/min
Monitoring: Monitor procainamide (4-10 mcg/mL) and NAPA levels (6-20 mcg/mL)
High NAPA:Proc ratio – fast acetylator
Lidocaine
Mechanism: Class Ib (weakest blockade)
Dosing: I.V.: 1 mg/kg bolus; infusion: mcg/kg/minute
Monitoring: Monitor lidocaine levels (1.5-5 mcg/mL)
Flecainide
Mechanism: Class Ic (strongest blockade)
Dosing: Oral: mg/m2/DAY divided every 8-12 hours
Monitoring: Monitor flecainide troughs ( ng/mL) – conjunction with ECG
Remember Class I antiarrhythmics work on the sodium channel within cardiac myocytes, reducing the rate of depolarization
Procainamide Adverse Effects:
Blood dyscrasias like agranulocytosis; weekly monitoring until 3 months
Conduction disturbances: first degree AV block
Hypotension
Drug induce lupus like syndrome (rising ANA titers)
Proarrhythmic effects: QTc prolongation
Negative inotrope: careful use in patients with depressed heart function, electrolyte imbalances (low potassium, low magnesium)
IV contains sodium metabisulfite: allergic type reactions
Optimal serum concentration (6-12 hours after infusion start): PA: 4-10; NAPA: 6-20 (15-25), toxicity observed in patients with PA level >10-12
Lidocaine Adverse Effects
CNS (tremor/seizure) and CV side effects
Caution in hepatic impairment, HF, hypoxia, respiratory depression, or shock. CI in WPW and severe SA, AV, or intraventricular block
Optimal serum concentrations (12 hours after starting; then every 24. Monitor Q12 if impaired renal/hepatic insufficiency): 1.5 – 5 mcg/mL
Flecainide Adverse Effects:
CNS (vision and parasthesias)

16. Class II (β-Antagonists)
Propranolol
Dosing: I.V.: mg/kg/DOSE Q6-8hrs; Oral: 1-4 mg/kg/DOSE Q6-8hrs
Special Formulations: commercially available liquid (4 mg/ml)
Metoprolol
Dosing: Oral: 1-6 mg/kg/DAY Q12hours
Special Formulations: Compounded liquid (10 mg/mL tartrate) – extended release tablets available (succinate)
Atenolol
Dosing: Oral: mg/kg/DAY (maximum 100 mg/DAY)
Special Formulations: Compounded liquid (2 mg/mL)
Esmolol
Dosing: I.V. Infusion: 150 – 1000 mcg/kg/min
Adverse Reactions:
GI disturbances, insomnia, nightmares, lethargy, erectile dysfunction, possible AV block in patients with AV node dysfunction

17. Class III (Potassium Channel)
Amiodarone
Mechanism:
Primary action is to prolong refractory period (K+ channel)
Calcium channel blockade
β-Antagonists
Na+ Channel blockade
Dosing:
IV Infusion: mg/kg/DAY for days, then maintenance dosing (oral): mg/kg/DAY
Monitoring
Can cause hypotension on IV administration (Polysorbate 80)
Hepatic injury, hypothyroidism, corneal deposits, skin sensitivity
Difficult to compound for outpatients
Only compatible in D5W (IV)

18. Class III (Potassium Channel)
Sotalol
Mechanism
K+ channel blockade (increasing refractory period)
Beta-blockade (decrease automaticity)
Dosing
mg/m2/day divided 2-3 times daily
Formulations
Oral and IV (new) formulations available
Monitoring
QT prolongation / Torsades des Pointes
Females > Males

19. Class IV (Calcium Channel)
Mechanism: Centrally acting (myocardium) calcium channel blockade
Not typically used in pediatric patients
Dosing:
Verapamil
IV: mg/kg (maximum 5-10 mg in children) every 30 minutes as needed
Diltiazem
IV: 0.25 mg/kg (15-20 mg) up to 0.35 mg/kg (20-25 mg); infusions: mg/hour
Use: Some children, adolescents, and adults with atrial fibrillation/flutter
Do not use in patients < 1 year of age
Cardiovascular collapse has been noted in patients

20. Digoxin Mechanism: AV node Dosing:
Decreases automaticity
Dosing:
IV: mcg/kg/DAY divided every 12 hours
Oral: 5-10 mcg/kg/DAY divided every 12 hours
Changes in exposure
Drug-drug interactions, renal function
Digoxin toxicity
Signs and symptoms under recognized
Monitoring: serum concentrations are rarely useful
Poor correlation with toxicity
Use: primarily to treat SVT in infants

21. Adenosine Mechanism: Blocks AV node Dosing
‘Re-sets’ re-entrant circuit SVT
Dosing
IV: mg/kg to maximum of 0.2 mg/kg (or 12 mg)
Administration: rapid IV push
Inject at site closest to heart
Must travel through circulation to coronary arteries
Monitoring
ECG should show ‘sinus pause’
Not effective – likely an ectopic focus
Use: Hemodynamically unstable patients with SVT
Short half-life: 5-10 seconds
Metabolized by red blood cells

22. Objectives
Understand the underlying theory for the use of antiarrhythmic medications
Understand the mechanism of action for commonly used antiarrhythmic medications used in pediatric cardiac intensive care
Recommend a plan to monitor patients on antiarrhythmic medications