4 - Pharmacology and Pharmaceutic Principles of Anti-Arrhythmic Drugs

What does hERG blockade have to do with long QT?

hERG blockade → decreasing K⁺ efflux → slower ventricular repolarization → prolonged QT interval → increase the risk of torsades de pointes

How does Ca²⁺ blockade affect long QT?

Long QT → increase the risk of EADs

Ca²⁺ blockade → decreases EADs → therefore decreases risk of Torsades

Why is anti-arrhythmic drug therapy dangerous?

Can worsen existing arrhythmias or cause new ones

Benefits must outweigh risks!

What is the main goal of anti-arrhythmic drugs?

Is to blunt/prevent → abnormal impulse formation and/or abnormal conduction

What are the 4 major classes of anti-arrhythmic drugs?

Class I → Na⁺ channel blockers

Class II → decreasing sympathetic activity → β-blockers

Class III → K⁺ channel blockers

Class IV → Ca²⁺ channel blockers in the heart

What are the therapeutic objectives of anti-arrhythmic drug therapy?

Alter one or more of the following:

• Effective refractory period (ERP)

• Rate of depolarization / repolarization

• Resting potential

What phase does Class I anti-arrhythmic drugs affect?

Phase 0

Depolarization → blocks Na⁺ channels

What phase does Class II anti-arrhythmic drugs affect?

Phase 2

Contraction → decreases contractility

What phase does Class III anti-arrhythmic drugs affect?

Phase 3

Repolarization → blocks K⁺ channels

What phase does Class IV anti-arrhythmic drugs affect?

Phase 2

Contraction → blocks Ca²⁺ channels

What phases do Class II and IV affect in SA/AV nodes?

Affect Ca+2

Affects depolarization of the SA/AV nodes

What is the role of Ca²⁺ in cardiac muscle?

It triggers cardiac muscle contraction

Why does cardiac relaxation require more ATP than contraction?

Ca²⁺ must be actively pumped back into the SR by SERCA (pump)

Requires ATP → ~55% of ATP use vs ~45% for contraction

What do CCBs do in cardiac muscle?

Block L-type Ca²⁺ channels (gateways that let Ca²⁺ enter cardiac muscle)

Decreasing Ca²⁺ entry → decreasing contraction → decreasing O2 demand

Why use CCBs cautiously with β-blockers?

Verapamil and diltiazem

They decrease contractility and cardiac output

With β-blockers, effects are additive → excessive decrease in HR and contractility

What are the 3 main CCB families?

Dihydropyridines (DHPs)

Phenylalkylamine

Benzothiazepine

What does the Dihydropyridine family mainly act on?

Mainly on vascular L-type Ca²⁺ channels

Ex → Nifedipine, amlodipine, nicardipine, felodipine

What does the Phenylalkylamine and Benzothiazepine families mainly act on?

Act as a non-selective block of cardiac and vascular Ca2+ channels

Phenylalkylamine → Verapamil

Benzothiazepine → Diltiazem

What are the Class IA antiarrhythmic drugs?

Quinidine

Procainamide

Disopyramide

MOA of Class IA antiarrhythmics?

Na⁺ channel blockade → decreases Phase 0 depolarization and Vmax → slows conduction velocity

Slower conduction + longer action potential → prevents abnormal impulses

What are the Class IB arrhythmic drugs?

Lidocaine

Phenytoin

Mexiletine

MOA of Class IB arrhythmic drugs?

Blocks Na⁺ channels, especially inactivated channels → slows Na⁺ channel recovery and increases the EFP

What are the Class IC drugs?

Flecainide

Propafenone

MOA of Class IC drugs?

Strongly blocks Na⁺ channels → greatly decreases Phase 0 depolarization / Vmax → slows conduction

Strong Na⁺ block + very slow conduction + no major AP change

Why is increasing the effective refractory period (ERP) good for treating arrhythmias?

It makes the cardiac cells stay unable to respond to new impulses longer

Abnormal impulses have a harder time spreadiing

Quinidine?

Class IA

Oral

Hepatic → will inhibit 2D6

Major adverse effects of quinidine?

Anticholinergic effect → cardiotoxic

Major drug-drug interactions with Quinidine?

CYP2D6 → some antidepressants, or macrolide antibiotics (mycin)

Digoxin

Procainamide?

Oral, IM, IV

CYP2D6

N-acetyltransferase enzyme coverts it into → acetylated to NAPA → NAPA can block K⁺ channels → TdeP

Major adverse effects of Procainamide?

Systemic lupus erythematosus (SLE)-like syndrome

Torsades de Pointes → due to increased NAPA

Major drug-drug interactions with Procainamide?

Cimetidine

Does not interfere with digoxin

Disopyramide?

Class IA

Oral

CPY3A4

Major adverse effects of Disopyramide?

Anticholinergic effect → cardiotoxic

Strong negative inotropic effect

Major drug-drug interactions with Disopyramide?

CYP2D6 → macrolide antibiotics (mycin)

Lidocaine?

Parenteral only → only 3% of oral appears in plasma due to rapid hepatic metabolism

IV preferred → can be IM

Major adverse effects of lidocaine?

Direct CNS effects at high doses → Seizures !

Major drug-drug interactions with lidocaine?

Drugs that decrease hepatic blood flow → B-blockers, cimetidine

Drugs that inhibit Cyto-P450 enzymes

Mexiletine?

Orally active conger of lidocaine → low first pass effect

Hepatic → CYP1A2, CYP2D6

Major side effects of Mexiletine?

Mostly GI

Neurologic → tremors, dizziness, psychosis, convulsions

Major drug-drug interactions with Mexiletine?

Anti-depressants → CYP1A2, CYP2D6

Theophylline → CYP1A2

How does lidocaine block cardiac Na⁺ channels?

Blocks inactivated Na⁺ channels more than open channels and dissociates rapidly (<1 sec)

Why does lidocaine selectively affect depolarized or rapidly firing cells?

Depolarized or rapidly firing cells have more Na⁺ channels in the inactivated state → lidocaine blocks these cells more strongly

Why are Class IB drugs useful for ischemic or cardiac glycoside-induced arrhythmias?

They preferentially target depolarized (“sick”) cardiac cells → helps treat arrhythmias in these damaged cells

Why are Class IC drugs considered highly pro-arrhythmic?

Study found a 2.5-fold increase in fatal arrhythmias in patients with a prior MI

Contraindicated in patients with history of MI or cardiac ischemia

Flecainide and Propafenone?

Class IC

Oral

Major adverse effects of Flecainide and Propafenone?

Contraindicated in patients with history of MI or cardiac ischemia

MOA Class II antiarrhythmics?

Block β1 receptors → decrease sympathetic activity → decrease heart rate and slow AV node conduction

MOA Class III antiarrhythmics?

Blocks K⁺ channels → slows repolarization → increases action potential duration, EFP and QT

MOA Class IV antiarrhythmics?

Blocks Ca²⁺ channels in nodal cells → decreases Ca²⁺ entry → slows AV node conduction and increases AV node refractory period

Examples of Class II drugs?

Propranolol

Metoprolol

Esmolol

Acebutolol

What beta blocker is ideal for rate control situations where a long acting BB is not ideal?

Esmolol → 9-minute half-life → ideal for rate control when a long-acting β-blocker is not ideal

What are Class II antiarrhythmics used for?

“Slow it down”

SVT and AFib/AFlutter rate control

How do Class II anti-arrhymics work?

Decrease HR and AV conduction

Adverse effects of Class II?

Potential to make heart failure worse

AV block

Sinus arrest

Bronchospasm in asthmatic patients

Example of Class IV drugs?

Calcium channel blockers!

Verapamil

Diltiazem

What are Class IV antiarrhythmics used for?

“Control the AV node”

SVT + AFib/AFlutter rate control

How do Class IV antiarrhythmics work?

Block Ca2+ → slows the heart + AV node

Adverse effects of Class IV drugs?

Bradycardia → possible AV block

Hypotension

Potential to make heart failure worse

Peripheral edema

GI issues

Amiodarone and Dronedarone membrane action?

slower + longer!!!

Slow everything + prolong QT

Amiodarone and dronedarone effect on EKG?

Slower and longer!

QT = longer; HR, PR, QRS = slower

Therapeutic uses of amiodarone and dronedarone?

Amiodarone → commonly used for post-operative arrhythmias.

Supraventricular + ventricular arrhythmias

How are amiodarone and dronedarone metabolized?

Liver → CYP3A4

Very long half-life →13–103 days

Vd: 60 L/kg

Dofetilide and Ibutilide membrane?

Increases refractory period → harder to fire again

Increases inward sodium channel

Decreases outward potassium channel

Dofetilide and Ibutilide effects on EKG?

Decrease sinus rate

Increase QT interval

Amiodarone?

Class III
Oral and IV in acute cases

Adverse effects of amiodarone?

Bradycardia or heart block

Increased risk of long QT

Pulmonary fibrosis

Corneal deposits

Hypothyroidism / Hyperthyroidism

Drug-drug interactions of Amiodarone?

Can increase serum levels of several Class I and → digoxin, warfarin, and statins

Dronedarone?

Class III

Oral

Dronedarone adverse effects?

Less toxic than amiodarone

Exacerbation of severe heart failure

Increased risk of long QT

Ibutilide and Dofetilide?

Class III
Oral and rarely IV

What classes does amiodarone act as?

Dual acting Class III + Class I

It also has mild β, α, and Ca²⁺ blocking effects

It is a mixture of all 4 classes

How does amiodarone stay in the body so long?

It is highly lipid-soluble → stored in fat, liver, and lungs.

It also has an extremely long half life → ~6 months

What is important to remember about amiodarone's safety?

It can cause serious side effects → so benefits must be weighed against risks

What is dronedarone?

Class III

An amiodarone analog with a much shorter half-life (1–2 days)

Thought to have fewer serious side effects than amiodarone → BUT it can worsen heart failure.

Sotalol / Betapace?

Dual acting class → Class II + III
Its stuck between the 2 classes

How is sotalol given and what is it used for?

Usually oral → ~100% bioavailable

Used for A-fib + severe ventricular arrhythmias

What are the major concerns with sotalol?

↑ QT → ↑ Torsades risk → Risk is higher with bradycardia, low K⁺, or low Mg²⁺

Few drug interactions

What is the main action of adenosine?

Transiently / briefly blocks Ca²⁺ channels → slows AV-node conduction

Activates K⁺ channels → hyperpolarizes the membrane

temporarily slows AV-node conduction and makes the membrane less excitable

How is adenosine given and what is it used for?

IV only → lasts only 10–15 seconds.

Used for AV-nodal reentry + paroxysmal SVT.

Adverse effects → Dizziness and shortness of breath

What is Mg²⁺ used for in arrhythmias?

Weakly blocks Ca²⁺ channels and affects Na⁺/K⁺ ATPase → useful for long QT, digitalis toxicity, and Torsades de Pointes.

What is K⁺ used for in arrhythmias?

Slows AV conduction → useful for digitalis toxicity and arrhythmias caused by electrolyte imbalance.

Electrolyte administration and adverse effects?

IV typically, K+ can be oral

Mg → muscle weakness

K → overdose can be pro-arrhythmic even fatal