• Beta-blockers
• Calcium channel blockers
• Digoxin 

• With advances in electro-cardiology, many of the arrhythmias that were previously treated with drugs are now being treated with electrical ablation therapy
• However, all patients cannot be treated successfully with ablation and in these circumstances need to be maintained on anti-arrhythmic drugs

In general terms, how to anti-arrhythmic drugs work?

What is the most important untoward affect to be aware of for anti-arrhymic drugs?

• Anti-arrhymic drugs work by altering membrane excitability.
• And since arrhythmias asrise from alterations of normal membrane excitability, these drugs have a significant potential for causing arrhythmias

What are 1C agents used for? 

What is the danger with this drug class?

• Effective for suppressing ectopic ventricular beats 
• HOWEVER, ectopic betas arise in ischemic tissue and so any patient w/ventricular ischemia is prone to develop lethal ventricular arrhythmias when treated with 1C agents. So the use of these can be really bad if used for ectopic beat suppression.  
• Following an MI, patients are much more likely to have an ectopic beat. So these came out to treat those, but data ended up showing showing that the use of 1C agents to suppress ectopic beats resulted in much greater mortality than leaving the ectopoic beats untreated 

• Class-1 (Class 1A; Class 1B; Class 1C)
• Class-2
• Class-3
• Class-4
• "Other agents" 

**Anti-arrhythmic drugs can fall into more than 1 class**

• Block Na+ channels 

• Block beta-1 receptors 

• Block K+ channels 

• Block Ca++ channels 

What drugs are in the "other" agent category for anti-arrhythmics?

And their MOAs...

• Adenosine:  Sometimes referred to as purinergic agent b/c they are purine receptor agonists that stimulate adenosine receptors 
• Digoxin:  Works by increasing vagal tone to slow SA and AV node depolarization while also increasing the rate of spontaneous depolarization in the purkinje fibers. When there is A-fib, and the patient is put on digoxin, the conduction is blocked at the AV-node allowing for purkinje system pacemaker to take over the rate-control.  However, the rate instead of being at 40 bpm, is about 50-60 bpm b/c of the spontaneous depolarization caused by digoxin in the ventricular tissue.  So removes the symptomatic atrial-fibrillation by closing the AV-node and causing a cease to the irregular pulses in the ventricles.  And increases the ventricular automaticity to improve CO. 

**THESE DRUGS INCREASE MORTALITY***

**SO THEY HAVE VERY LIMITED USE***

• All of the drugs in this class block Na channels (more highly selective for cardiac sodium channels).  
• Many of the drugs in this class bind to Na channels in either the open or inactivated state and do not bind to and dissociate from closed Na channels.  So they are going to selectively bind to and block the Na channels that can actually cause a depolarization to occur.  So these drugs are particularly effective against high-frequency arrhythmias. Since the heart is a syncytium, slowing the rate of depolarization in one cell slows the spread of depolarization across the heart.  When rates are high (SVT or VT), these agents slow that rate down.  
• This is going going to slow the rate of depolarization (action-potential)

Class-1A agents:

• Quinidine 
• Procainamide 

Class-1B agents:

• Lidocaine 
• Mexiletine 

Class-1C agents:

• Flecainide 
• Propafenone
• Moricizine 

**Class-1A**

• Only historical interest b/c of classical toxicity 
• Na-channel blocker + anti-cholingergic (blocks muscarinic receptors) 
• Know that the anti-muscarinic receptor mechanism occurs BEFORE the anti-arrhythmic class-1A affect of Na-channel blocker.  So in a person with A-fib, before giving quinidine, you MUST block the AV node (digoxin).  B/c when you give quinidine, the anti-arrhythmic effect does not kick in right away and you have decreased PS tone to the AV-node which can potentially cause letha ventricular tachycardia.  Within a few minutes is when you see the anti-arrhythmic affect of class-1A drugs and then pulses no longer come through the AV node as readily.  So digoxin protects against this SVT 

Procainamide MOA (detailed) 

Untoward effects

**Class-1A**

• Still remains in use but very limited in use
• Eliminates tachycardia associated with Wolff-Parkinson-White Syndrome
• Also used to treat other high-frequency arrhythmias (VT, A-Fib, A-Flutter) 
• Has slight vagus blocking properties but these are over-ridden by its class-1A affect

**Class 1B agent**

**Blocks Na-channels**

• This is a DISTANT 2nd choice to cardioversion
• Used as local anesthetic of dentristy but also used as an anti-arrhythmic 
• Neuronal tissue is sensitive to the membrane altering effects of this drug. And often, if given in large doses, causes the release of GABA by small neurons and causes impairment of neuronal conduction in the CNS. 
• used for ventricular arrhythmias such as VT but no use in supraventricular arrhythmias

Lidocaine ROA 

Half-Life

Untoward effects

Mexiletine MOA

Use

**Class-1B**

• This is the oral form of lidocaine
• Used primarily for people who do not want to use an ICD b/c of the pain associated with the shock.  It is most effective, like lidocaine, on VT and is not effective against SVT

• Flecainide 
• Propafenone 
• Moricizine 

Class-1C agent use

Untoward effects

• Came to the market as PVC-killers w/the fewest side-effects but that was NOT the case b/c patients died at higher rates on these drugs especially individuals that had previous ventricular damage due to ischemia 
• Are known to cause long-QT syndrome and can lead to torsade de pointes 

Uses

• Atrial fibrillation, limited to maintaining normal sinus rhythm in patients who have been converted from A-fib to normal sinus rhythm. But primary choice is to use ablation therapy instead of this.  
• Distant second choice for treatment of SVT of junctional origin

• 1st DOC:  Diltiazem 
• 2nd DOC:  Beta-blockers or Verapamil 
• 3rd DOC:  Amiodarone 

Class-2 Anti-Arrhythmic Agents

Use

**Class-2 = beta blockers**

Use:  Rate control + depress ectopic foci

• Used for A-flutter; A-fib; Multi-focal-atrial tachycardia (but diltiazem is used much more readily for these...it is the DOC) 
• Used for prophylactic treatment against SVT of junctional origin 
• Improve mortality in post-MI patients by suppressing VT 
• They slow the SA node + slow spontaneous discharge of the AV-node
• They decrease conduction of pulses through the AV node 
• During A-fib, they are used to decrease conduction through the AV-node and control the ventricular rate that way

**Class 3 = K+ channel blockers**

• Amiodarone
• Dronedarone 
• Sotalol 
• Ibutilide 

Amiodarone MOA 

Uses

Dosing

**Class-3 drug that blocks potassium channels**

• Although this drug is a class-3 drug, it also has class-1, 2, and 4 effects
• Uses:  Atrial and ventricular arrhythmias (A-fib + A-flutter + VT)
• Dosing:  Has a HUGE volume of distribution so these drugs require a LARGE loading dose instead of taking maintenance doses intially b/c it would take days.  Since it has such a large volume of distribution, if the patient presents with untoward effects, it is going to take the body a few days to get rid of the drug as well.  

1. "Smurg Drug" b/c turns skin blue (permanent!!!)
2. Pulmonary fibrosis in 1%; DOSE RELATED, keep dose low! (can be lethal)
3. Liver Damage 
4. Occular changes, corneal deposits, halos around objects, vision destroying optic neuritis 
5. Can effect the thyroid 

Dronedarone

MOA

Use 

Resemblance to amiodarone

**Class 3**

• Structural analog of amiodarone w/o iodination 
• Resembles amiodarone but w/o thyroid effects and is NOT associated w/pulmonary fibrosis

• Do NOT use in class-IV HF
• Do NOT use in patients with class-II or III HF who experience acute decompensation failure 
• Essentially do NOT give to patients w/class-III HF b/c you are going to expect that these patients will have decompensation episodes 

Sotalol 

MOA

Use 

SE 

**Class-3 anti-arrhytmic**

Although this is a non-selective beta-blocker, it is still classified as a class-3 anti-arrhythmic b/c it has significant K+ channel blocking 

• MOA:  Unique b/c decreases energy required to produce defibrillation.  It is classified as a class-3 b/c causes dose related torsade-de-pointes unlike beta-blockers
• Use:  Maintain normal rhythm in patients that have converted from A-fib; treatment for VT 

Ibutilide

• However, this is still far down the list of options b/c a-fib and a-flutter often recur after administration of ibutilide conversion and is often used after ablation and rate-control mechanisms have been tried w/beta-blockers and Ca++ channel blockers
• The BEST method for establishing normal sinus rhythm in patients that have a-fib/a-flutter is by ablating the tissue that is responsible for the dysrhythmias 
• If ablation fails then next step is to rate control w/beta-blocker or Ca++ channel blocker 
• If that doesn't work, then try ibutilide 

Ibutilide 

Use

SE

**Class-3 anti-arrhythmic***

• Use:  Most effective pharmocologic agent for converting atrial fibrillation to normal sinus rhythm.  Can also convert atrial flutter w/good efficacy.  This drug is down the list of options, but does offer the best chance of all anti-arrhythmic drugs for establishing normal sinus rhythm.  

Class-4 anti-arrhythmic drugs

Which one is used more often? Why?

Class-4 Drugs 

Use 

Untoward effects 

• Use:  Control ventricular rate in atrial fibrillation; atrial flutter; also used in multi-focal tachycardia; junctional tachycardia 

• Untoward effect:  Excessive AV block 

Adenosine 

Use

Use:  Terminate AV nodal re-entrance tachycardia 

Adenosine 

Half-life 

Effectiveness

Untoward effects 

• Half-life:  10 seconds so drug action is terminated quickly after IV bolus is given 

• Effectiveness:  Adenosine receptors are the target for caffeine and peole who drink large amounts of caffeine or theobromine (cousin of caffeine in tea and chocholate) may not see a benefit 

Digoxin 

Use

• B/c the AV blocking properties of digoxin can be easily overcome by sympathetic stimulation, digoxin has little use in atrial fibrillation other than in those patients w/systolic heart failure 
• Has numerous untoward effects 
• Used for A-fib b/c it seals the AV node and also increases ventricular automaticity and contractility

Class-1B drugs 

Lidocaine 

Mexiletine