Antiarrhythmic Pharmacology

Created by: Nicholas B Norgard, PharmD

Animated Nick Norgard Nation monogram

Course orientation · Seven-step drug framework

Use the same reasoning chain for every antiarrhythmic.

A quick refresher—not a new framework

1

Target

Where does the drug act?

2

Action

What does it do there?

3

Tissue effect

What changes directly?

4

Body response

How does the body respond?

5

Uses and outcomes

Who benefits, and how?

6

Safety

What could go wrong, and why?

7

Pharmacokinetics

Does exposure change the prediction or decision?

In this lecture

We will highlight the one or two steps that do the most explanatory work for each drug, then reconnect them to the complete chain.

Foundations · 0.1

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ACTION POTENTIAL: The Drug Target Map

To Know Antiarrhythmics, You Have to Know the Action Potential

Fast-response tissue

Atrial · ventricular · His–Purkinje

Phase Current Event
0 INa Upstroke. Rate of rise sets conduction velocity.
1 Ito Notch.
2 ICaL vs IK Plateau. Ca²⁺ entry triggers contraction.
3 IKr, IKs Repolarization. Major determinant of APD and QT.
4 IK1 Stabilizes rest; also contributes to terminal repolarization.

Slow-response tissue

SA node · AV node

Phase Current Event
0 ICaL Slow upstroke; sets nodal conduction velocity.
1 — Absent: no notch.
2 — Absent: no plateau.
3 IK Repolarization to maximum diastolic potential.
4 If, ICaT Spontaneous depolarization toward threshold.
Annotated fast-response action potential showing phases zero through four and their principal ionic currents.
Fast response — atrial, ventricular, His–Purkinje
Annotated slow-response nodal action potential showing spontaneous phase four, calcium-dependent phase zero, and potassium-dependent phase three.
Slow response — SA and AV node

Different tissue → different current → different pharmacologic target.

Foundations · 0.2 · Channel states

FAST Na⁺ CHANNELS: Excitable, Excited, Refractory

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Fast sodium channel state cycle showing resting available, activated open, and inactivated refractory conformations with recovery during repolarization.
The refractory clock is a channel-state cycle: available → open → inactivated → recovered and available again.
Core distinction

Closed does not always mean ready: a resting channel is excitable; an inactivated channel is refractory.

Foundations · Mechanisms of arrhythmia

An arrhythmia begins when impulse generation or propagation goes wrong.

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First ask what created the impulse. Then ask what allows it to continue.

01

Impulse generation

Why did a cell fire?

Automaticity
Spontaneous phase-4 depolarization reaches threshold without a preceding action potential; when a site outside the normal dominant pacemaker fires first, it acts as an ectopic pacemaker.
Triggered activity
A preceding action potential is required: an EAD interrupts repolarization; a DAD follows it.
02

Impulse propagation

Why did the wavefront conduct—or fail?

Conduction delay or block
The impulse slows, becomes decremental, or fails to traverse a region of tissue.
Reentry
A wavefront returns to previously activated tissue after that tissue has recovered excitability.
Initiation and maintenance can differ. An ectopic or triggered beat may start an arrhythmia that is then sustained by reentry.
Mechanistic question

What started the rhythm—and what keeps it going—may have two different answers.

Foundations · 0.6 · Reentry

Reentry needs all three.

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1

Two pathways

Anatomically or functionally distinct

2

Unidirectional block

One pathway blocks in one direction

3

Sufficient delay

The returning pathway recovers in time

Four-panel diagram showing a substrate with two conduction pathways, a premature trigger encountering unidirectional block, delayed conduction through recovered tissue, and repeated circulation around the circuit.
Reentry requirement

Reentry is a timing problem: the returning wavefront must find tissue that has recovered excitability.

Final synthesis · Step 1 study priorities

What matters most for Step 1?

Reserved for the final lecture close Deferred
  1. 01

    Start with cell physiology.

    Separate fast-response atrial, ventricular, and Purkinje tissue from slow-response SA and AV nodal tissue.

  2. 02

    Map each current to an action-potential phase.

    Fast cells: Na⁺ phase 0, Ca²⁺ phase 2, and K⁺ phase 3. Nodal cells: Ca²⁺ phase 0 and spontaneous phase 4.

  3. 03

    Predict the ECG effect from the target.

    AV-nodal slowing lengthens PR; Na⁺-channel block widens QRS; delayed repolarization lengthens QT and raises torsades risk.

  4. 04

    Reason by class—not just drug name.

    Distinguish IA, IB, and IC; connect II and IV to the AV node; connect III to longer action-potential duration and refractoriness.

  5. 05

    Recognize the defining vignette patterns.

    Amiodarone toxicity, flecainide after MI, adenosine-sensitive SVT, digoxin toxicity, torsades, and pre-excited AF.

  6. 06

    Study in a mechanism-first sequence.

    Master channels, tissue, refractory periods, reentry, and ECG; then class signatures; then mechanism-based vignettes. De-emphasize exact doses and detailed prescribing.

Core approach

Connect target → tissue → action-potential phase → conduction or refractoriness → ECG → one defining clinical or toxicity pattern.

Step 1 → Step 2 · Foundations to drugs

The class label is the starting point—not the mechanism.

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Lei modernized Vaughan–Williams map: read across from target → electrophysiologic effect → ECG clue → representative agents.

The IIa/IId/IIe extensions are not standard Step 1 nomenclature. Real drug behavior still depends on state, kinetics, secondary targets, rate, and substrate.

Class Subclass / group Dominant target Electrophysiologic effect ECG clue Representative agents
INa⁺ IaIbIc Nav1.5State preference + recovery kinetics Fast-tissue conduction ↓
Post-repolarization refractoriness ↑Ia also delays repolarization		 QRS ↑Ia: QT ↑ Ia procainamide, quinidine, disopyramide
Ib lidocaine, mexiletine
Ic flecainide, propafenone
IISignals IIa β antagonistsIId vagal/ACh → M₂IIe adenosine → A₁ G-protein signalingGs and Gi pathways Pacemaker drive ↓
AV conduction ↓; nodal ERP ↑		 PR ↑Rate often ↓ IIa metoprolol, propranolol, esmololIId digoxinIIe adenosine
IIIK⁺ IKr-directedMultichannel Repolarizing K⁺ currentsIKr-directed versus multiple K⁺ currents and secondary targets Ventricular APD ↑
ERP ↑		 QT ↑ IKr-directed dofetilide, sotalol, ibutilideMultichannel amiodarone, dronedarone
IVCa²⁺ L-type blockers L-type Ca²⁺ channelsNodal phase 0 AV nodal conduction ↓
nodal ERP ↑		 PR ↑ Verapamil
diltiazem
Classification is orientation, not explanation. Sotalol also blocks β receptors, ibutilide also enhances a slow inward current, and the multichannel drugs differ substantially in efficacy and safety.
Next question

Use Vaughan–Williams for orientation; predict the drug from its target, kinetics, secondary actions, rate, and substrate.

Class I · Fast Na⁺-channel blockers

Class I begins with a moving target.

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The fast Na⁺ channel changes conformation every beat. A drug’s effect therefore depends on when it binds and whether it leaves before the next impulse.

01

Channel state

Resting · open · inactivated

02

Binding kinetics

Association + dissociation

03

Activation rate

How often the channel cycles

RESULT

Channels available next beat

Phase-0 dV/dt · conduction · refractoriness

“Sodium-channel blocker” is not yet an explanation. State preference and recovery from block are what make Ia, Ib, and Ic behave differently.

Next question

When during the beat can the drug bind—and is it still there when the next impulse arrives?

Class I · Electrophysiologic effect · Post-repolarization refractoriness

Voltage can recover before excitability does.

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The membrane-voltage clock and the channel-availability clock can separate.

ERP > APD90
Membrane potential +30 −90 APD₉₀ ERP APD₉₀ · voltage landmark ERP · propagation test PRR VOLTAGE ≥90% REPOLARIZED PROPAGATION NOT YET RECOVERED
APD90 is a standardized 90%-repolarization landmark—not a claim that the final 10% of repolarization is complete.
1

APD90: measure voltage

The membrane has completed 90% of its return toward resting potential. This defines a reproducible action-potential duration.

2

PRR: voltage is not enough

With Class I block, a sufficient fraction of Nav1.5 channels can remain drug-associated and unavailable. A premature impulse may therefore fail to propagate despite substantial repolarization.

3

ERP ends when propagation returns

ERP is defined operationally with a premature-stimulus test. It ends only when enough available fast Na⁺ current has recovered to support a propagated response.

Key relationship

PRR is the positive interval ERP − APD₉₀: the voltage clock reaches its 90% landmark before propagation recovers.

Class Ia

Class Ia changes two currents.

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Key takeaway

Class Ia is not a single-current mechanism.

Class Ib

Class Ib selects the substrate.

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Key takeaway

Fast recovery spares well-polarized tissue; depolarized ventricular tissue retains more block.

Class Ic

Class Ic block persists between beats.

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Key takeaway

Slow recovery from block reduces conduction reserve beyond membrane repolarization.

Class II

Class II changes nodal signaling.

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Key takeaway

Class II drugs alter pacemaker and AV-nodal behavior through receptor signaling.

Class III

Class III prolongs repolarization.

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Key takeaway

The shared Class III label does not imply a shared clinical profile.

Class IV

Class IV targets calcium-dependent nodal conduction.

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Key takeaway

Class IV acts directly on nodal L-type calcium channels.

Foundations · 0.1

Every phase is a current.

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Preparing the action-potential model…
Key takeaway

Working myocardium has a stable phase 4 and waits for a propagated stimulus.