Pharmacology I: 4.8 Anti-Arrhythmia

How do arrhythmias arise?

As a result of electrical dysfunction in cardiac tissues

What can result in electrical dysfunction?

- SA/AV node

- Cardiomyocytes

- Genetic variants in channels

- Ischemic damage

What are cardiomyocytes made up of?

- Bundle branches

- Purkinje cells

Defect in either impulse formation

- Automaticity

- Triggered activity (EAD, DAD)

Automaticity

- Increase slope of phase 4 which increases HR

- Increase in threshold potential which decreases HR

Conduction

- Re-entry

- Conduction block

- Accessory pathways

Triggered activity is more likely to happen in what kind of tissue?

Damaged

EAD

early after depolarization

EAD is composed of?

- Sodium channels recover and are activated

- Triggers an action potential

DAD

delayed after depolarization

DAD is composed of?

- Ca++ overload in cytoplasm

- NCX pumps excess Ca++ out of cell in exchange for Na+

- Na+ influx can trigger an action potential

What is an abnormal conduction in re-entry?

Split in electrical pathway

What can. damage causes conduction block in what direction?

One direction

How can an electrical impulse come back around?

- Wrong direction

- Wrong rate (too fast)

- Not under control of SA node

What does symptoms depend on?

location

How should AV Septum be?

Complete insulating

Conduction only via?

AV node/bundle of His

Weak spot- bundle of Kent

- Can become conductive

- Anatomical re-entry circuit

- Abnormally fast heart rate

Wolf Parkinson White Arrhythmia

Normally treated with ablation

Sodium channel blockers examples?

procainamide, lidocaine, flecainide

What is the MOA of sodium channel blockers?

Non-competitive inhibition of Na+ channels which decreases conduction velocity

How is Procainamie administered?

- IV: Pronestyl

- PO: Procanbid DR

What is the half life of Procainamide?

3-4 hours

What is the MOA of procainamide?

Binds to and inhibits voltage gated Na+ channels

What does binding to the sodium gated channels do?

• Moderate-length Na+ channel blockade

• Use-dependent- binds to active channel

• Increases Slope of phase 0

• ↑ threshold for excitation --> increase conduction velocity

What is the active metabolite for Procainamide?

N-acetyl procainamide

What is acetylated?

At phenyl-amine

What does it bind to?

And inhibits outward K+ channels

What does this inhibition of K+ channels do?

- Increases effective refractory period esp. in atria

- Increases QT interval

What is potency like for procainamide?

Greater potency on the most active cells those driving the arrhythmia

How is procainamide excreted?

- 50% excrete unchanged

- 35% N-acetyl procainamide

Amid isostere of ester do?

Reduces metabolism which increases half-life as compared to procaine

What are the uses for procainamide?

• Symptomatic premature ventricular contractions

• Life threatening ventricular tachycardia

• Maintenance of normal sinus rhythm after conversion of atrial flutter

• Malignant hyperthermia

What are the adverse effects of Procainamide?

• Torsades de Pointes, AV block, ventricular tachycardia

• Hypotension

• Lengthening of QT interval, PVC's, tachycardia

• Hepatotoxicity

• Fatigue, headache, dizziness

• Agranulocytosis, thrombocytopenia

• Acute asthma attack, respiratory arrest

• Angioedema, systemic lupus-like syndrome (very common after long use)

• Cinchonism- neural, ototoxicity, retinal toxicity can be permanent

How is lidocaine administered?

IV administration

What is the half-life of lidocaine?

20 min

What is the MOA of lidocaine?

Na+ channel blocker

What does blocking the channel blocker do?

• Mid-length Na+ channel blockade

• Best for rapidly-driven tissues (use-dependent)

• Little effect on normal tissue

What does it effect?

Cardiac tissue

When lidocaine affects cardiac tissue, what happens?

- Decrease in automaticity via decrease phase 4 slope

- Shortens refractory period slightly

Where is lidocaine mainly used in?

Ventricular arrhythmias

What is the atria AP like?

Too short to be effective in atria

How is lidocaine metabolized?

liver by:

- First pass

- De-ethylation, CYP1A2

What does lidocaine not have an effect on?

QT interval, safe in patients with long QT syndrome

What are the uses of lidocaine?

• Ventricular arrhythmias

• Local anesthesia at injection site, pain, burning, itching

• Postherpetic neuralgia

What are the adverse effects of lidocaine?

• Seizures, confusion, dizziness (crosses BBB)

• Hypotension, bradycardia, arrhythmia, asystole, cardiac arrest

• Hepatotoxicity, GI upset, anaphylaxis, methemoglobinemia

• Restlessness, stupor, tremor, vision problems, tinnitus, nervousness

How is flecainide administer?

Orally

What is the half-life for flecainide?

12-30 hr

How is flecainide administered?

Extensive CYP2D6 with renal excretion

What is the MOA of Flecainide?

Na+ channel blockade

What does blocking of the Na+ channel do?

• Long Na+ channel blockade (strongest of the 3)

• Decreases Slope phase 0

--• Suppresses ventricular PVC's

• Decreases Conduction velocity

--• Significant suppression of cardiac function

--• Pro-arrhythmic adverse effects

What does flecainide not have an effect on?

Refractory period

What are the uses for flecainide?

• Black box warning: use only in life-threatening arrhythmia

• Sustained ventricular tachycardia

• Paroxysmal supraventricular tachycardia

• Paroxysmal atrial fibrillation

What are the adverse effects of flecainide?

• Cardiac arrest, heart failure, serious arrhythmia, conduction block

--• Increases PR and QT intervals

• Agranulocytosis, thrombosis

• Hepatomegaly, systemic lupus, anemia, stroke, renal failure, respiratory failure, impotence

• Dizziness, headache, syncope, nausea, visual disturbances, dyspnea

What are the cellular effects of anti-arrhythmias?

- Decrease in conduction velocity

- Decrease in Phase 4 slope (which decreases firing rate)

- Increase in threshold potential

- Increase in AP duration (1A only) due to inhibition of Ikr

What are the organ level effects of anti-arrhythmias?

- Decreases automaticity

- Decrease in early depolarizations

- Decrease delayed after-depolarizations

- Suppress electrical re-entry

Decrease in automaticity leads to?

- Suppress ectopic foci

- Decreases HR

Decrease in early after-depolarizations and delayed after-depolarizations

Suppress ectopic foci