Antiarrhythmic Medicinal Chemistry – Core Vocabulary

These flashcards introduce foundational vocabulary from the Antiarrhythmic Medicinal Chemistry lecture, covering arrhythmia types, antiarrhythmic drug classes, representative agents, structural requirements, metabolism, and key pharmacokinetic concepts.

Arrhythmia

Any abnormality in the rate or rhythm of the heartbeat.

Bradycardia

A type of arrhythmia characterized by an abnormally slow heart rate.

Tachycardia

A type of arrhythmia defined by an abnormally fast heart rate.

Flutter / Fibrillation

Rapid, irregular heart rhythms that can reduce cardiac efficiency.

Premature Ventricular Contraction (PVC)

An early heartbeat originating in the ventricles, often felt as a skipped beat.

Class I Antiarrhythmics

Sodium-channel blockers used mainly for ventricular arrhythmias.

Class II Antiarrhythmics

β-blockers that slow heart rate by blocking adrenergic stimulation.

Class III Antiarrhythmics

Repolarization prolongers that extend action-potential duration, often via K⁺-channel blockade.

Class IV Antiarrhythmics

Calcium-channel blockers that slow AV conduction and reduce vascular resistance.

Class Ia Agents

Intermediate-strength Na⁺-channel blockers (e.g., quinidine, procainamide, disopyramide).

Class Ib Agents

Mild Na⁺-channel blockers (e.g., lidocaine, mexiletine, tocainide).

Class Ic Agents

Strong Na⁺-channel blockers (e.g., flecainide, propafenone, indecainide, pilsicainide).

Quinidine

Natural product, diastereomer of quinine; Class Ia agent that also blocks α-receptors; extensively metabolized by CYP3A4 and inhibits CYP2D6 and P-gp.

Procainamide

Class Ia agent metabolized by acetylation to NAPA; slow acetylators risk drug-induced lupus; available IV for acute use.

Disopyramide

Racemic Class Ia agent with low protein binding; CYP3A4 metabolism; anticholinergic side effects such as dry mouth and constipation.

Lidocaine

IV Class Ib agent with rapid hepatic (CYP3A4) metabolism; useful for acute ventricular arrhythmias.

Mexiletine

Oral Class Ib analog of lidocaine; metabolized by CYP1A2 and CYP2D6.

Tocainide

Oral Class Ib agent cleared by both liver and kidney; longer half-life than lidocaine.

Flecainide

Potent Class Ic agent; CYP2D6 metabolism; long half-life (13-30 h).

Propafenone

Class Ic Na⁺-channel blocker with additional β-blocking activity; metabolized by CYP2D6 to 5-hydroxypropafenone.

Amiodarone

Class III agent with very long half-life (up to 107 days); extensive CYP3A4 metabolism to DEA; can cause thyroid, lung, and neurotoxicity.

Dronedarone

Amiodarone analog with shorter half-life (13-19 h) and reduced thyroid, lung, and neurotoxic effects; CYP3A4 substrate.

Sotalol

Non-selective β-blocker that also exhibits Class III action; renally excreted unchanged.

β-Blocker

Drug that inhibits β-adrenergic receptors, reducing heart rate and contractility (Class II antiarrhythmic).

Repolarization Prolonger

Agent that extends cardiac action-potential duration, typically by blocking K⁺ channels (Class III).

Calcium-Channel Blocker

Drug that inhibits L-type Ca²⁺ channels, decreasing AV conduction and causing vasodilation (Class IV).

1,4-Dihydropyridine (1,4-DHP)

Core scaffold of many Ca-channel blockers; requires Me (or larger) at C-2/6, esters at C-3/5, and aryl at C-4 for optimal activity.

Nifedipine

Prototype 1,4-DHP Ca-channel blocker; ortho-nitro phenyl at C-4; rapid onset via CYP3A4-metabolized nitro derivative.

Amlodipine

Basic 1,4-DHP with long half-life and high bioavailability; can be formulated for IV use due to basic side chain.

Verapamil

Phenylalkylamine Ca-channel blocker; strong effect on AV node; extensive hepatic metabolism.

Diltiazem

Benzothiazepine Ca-channel blocker; intermediate AV-node and vascular effects; hepatic clearance.

CYP3A4

Major hepatic cytochrome P450 isoform responsible for metabolism of many antiarrhythmics and Ca-channel blockers.

CYP2D6

Cytochrome P450 isoform inhibited by quinidine; metabolizes flecainide, propafenone, mexiletine.

N-Acetylprocainamide (NAPA)

Active metabolite of procainamide formed via acetylation.

N-Desethylamiodarone (DEA)

Major active metabolite of amiodarone.

Drug-Induced Lupus

Autoimmune-like syndrome linked to slow acetylation of procainamide.

Protein Binding

Fraction of drug bound to plasma proteins; high binding (e.g., quinidine ~80 %) affects distribution and DDI potential.

Half-Life (t½)

Time required for plasma concentration of a drug to decline by half; varies from hours (lidocaine) to days (amiodarone).

First-Pass Metabolism

Initial hepatic metabolism that reduces oral bioavailability, notable for 1,4-DHPs via CYP3A4.

Nitro Derivative

1,4-DHP with a nitro group on the aryl ring, generally increasing absorption and onset speed (e.g., nifedipine).

Pharmacophore

Minimal structural features required for a drug’s biological activity, such as the O–C–(CH2)2–N pattern in Class I agents.

Anticholinergic Effects

Side effects like dry mouth and constipation, often produced by Class Ia drugs such as disopyramide.

Vasodilation

Widening of blood vessels; primary effect of Ca-channel blockers, especially DHPs.

Drug–Drug Interaction (DDI)

Pharmacokinetic or pharmacodynamic alteration of one drug by another, common with CYP3A4 substrates or inhibitors.

Premature Ventricular Contraction (PVC)

Isolated early depolarization in ventricles causing an ‘extra’ beat.

Pharmacokinetics (PK)

Study of drug absorption, distribution, metabolism, and excretion; crucial for dosing antiarrhythmics.