Antiarrhythmic Drugs

Antiarrhythmics modify cardiac ion-channel and receptor activity to suppress abnormal automaticity and re-entry. They are among the most heavily tested pharmacology topics in NEET PG because of the Vaughan-Williams scheme, drug-of-choice questions, and the notorious proarrhythmic and extracardiac toxicities (especially amiodarone). Master the classification, the action-potential effects, and the arrhythmia-specific DOC, and most questions become answerable.

Cardiac action potential — the substrate

Understanding the ventricular/Purkinje action potential is mandatory because every class maps onto a phase.

Phase	Event	Main current
0	Rapid depolarisation (upstroke)	Fast Na⁺ influx (I_Na)
1	Early partial repolarisation	Transient K⁺ efflux (I_to) + Cl⁻
2	Plateau	Ca²⁺ influx (L-type) balanced by K⁺ efflux
3	Repolarisation	K⁺ efflux (I_Kr, I_Ks)
4	Diastolic depolarisation (pacemaker)	I_f "funny" Na⁺ + Ca²⁺ in SA/AV node

High-yield: SA and AV nodal cells have NO fast Na⁺ channels; their upstroke (phase 0) is Ca²⁺-dependent. Hence Class IV (Ca²⁺ blockers) and Class II (β-blockers) act mainly on nodal tissue, slowing AV conduction.

Vaughan-Williams classification

This four-class scheme is the single most examined fact.

Class	Mechanism	Prototype drugs	Main AP effect
IA	Moderate Na⁺ block + K⁺ block	Quinidine, Procainamide, Disopyramide	↓Phase 0, ↑APD, ↑QT
IB	Weak Na⁺ block (fast on-off)	Lidocaine, Mexiletine, Phenytoin	↓APD slightly, little ECG change
IC	Strong Na⁺ block (slow off)	Flecainide, Propafenone	Marked ↓Phase 0, ↑QRS
II	β-adrenergic blockade	Propranolol, Metoprolol, Esmolol	↓Phase 4 slope, ↑AV refractoriness
III	K⁺ channel block	Amiodarone, Sotalol, Dofetilide, Ibutilide, Dronedarone	↑APD, ↑ERP, ↑QT
IV	L-type Ca²⁺ block	Verapamil, Diltiazem	↓AV conduction, ↑AV ERP

Mnemonic for Class I subgroups (effect on APD): "A makes it Apart, B makes it Brief, C is the Same." IA lengthens APD, IB shortens it, IC has minimal effect.

Singh-Vaughan-Williams is the eponym; Bramah Singh added Class III. The newer Sicilian Gambit classifies by channel/receptor/pump target but is rarely tested beyond the name.

High-yield: Drugs that prolong QT and risk torsades = IA + III (quinidine, procainamide, disopyramide, sotalol, dofetilide, ibutilide). Amiodarone prolongs QT yet rarely causes torsades.

Class I — sodium-channel blockers

Class IA

• Quinidine: ↑QT, cinchonism (tinnitus, headache, vertigo), thrombocytopenia, diarrhoea. Has anticholinergic (vagolytic) action → can paradoxically ↑ ventricular rate in AF unless AV node controlled first. Inhibits CYP2D6 → ↑digoxin levels (quinidine-digoxin interaction).
• Procainamide: metabolite NAPA has Class III action; chronic use → drug-induced SLE (anti-histone antibodies, more in slow acetylators). DOC consideration in some stable wide-complex/WPW tachycardias.
• Disopyramide: strongest negative inotrope and most anticholinergic (dry mouth, urinary retention, constipation, glaucoma flare). Used in HOCM for its negative inotropy.

Class IB

• Lidocaine: acts preferentially on ischaemic/depolarised tissue (use-dependence); negligible effect on normal atrial tissue → ineffective in atrial arrhythmias. IV only (high first-pass). Toxicity: CNS — perioral numbness, tremor, seizures, then respiratory depression.
• Mexiletine: oral lidocaine analogue.
• Phenytoin: classic for digoxin-induced ventricular arrhythmias.

High-yield: Lidocaine = traditional drug for ventricular arrhythmias post-MI, but amiodarone is now preferred in shock-refractory VF/pulseless VT (ACLS). Lidocaine is useless for SVT/AF.

Class IC

• Flecainide, Propafenone: potent, markedly slow conduction. Used for AF cardioversion ("pill-in-the-pocket") and SVT in structurally normal hearts.

High-yield: CAST trial — flecainide/encainide increased mortality post-MI. ⟹ Class IC contraindicated in structural heart disease / post-MI / ischaemia.

Class II — beta-blockers

Block β1 → ↓cAMP → ↓I_f and ↓Ca²⁺ current in nodal cells → ↓SA rate, ↓AV conduction, ↑AV refractory period.

• Esmolol: ultra-short acting (esterase-metabolised, t½ ~9 min) → titratable for perioperative/thyrotoxic tachyarrhythmia.
• Uses: rate control in AF/flutter, SVT, exercise/catecholamine-induced arrhythmias, and mortality benefit post-MI and in heart failure.

High-yield: Only β-blockers (Class II) and amiodarone have proven mortality reduction in arrhythmia/HF settings; most Na⁺-channel blockers do not.

Class III — potassium-channel blockers

Amiodarone — the most tested single drug

Although classed III, it has all four class actions (Na⁺, β, K⁺, Ca²⁺ block) — broad-spectrum and effective for almost any tachyarrhythmia. Very long half-life (weeks–months) due to high lipophilicity and tissue accumulation.

Toxicity — learn cold:

System	Toxicity
Lung	Pulmonary fibrosis (most feared)
Thyroid	Both hypo- and hyperthyroidism (contains iodine; AIT type 1 & 2)
Eye	Corneal microdeposits (almost universal, benign), optic neuropathy
Skin	Blue-grey/slate discolouration, photosensitivity
Liver	Transaminitis, hepatitis
Neuro	Peripheral neuropathy, tremor
Heart	Bradycardia, ↑QT (low torsades risk)

High-yield: Amiodarone causes pulmonary fibrosis, corneal microdeposits, and thyroid dysfunction — a classic single-best-answer triad. Monitor TFT, LFT, and CXR/PFT. It inhibits CYP → raises warfarin and digoxin levels.

• Dronedarone: non-iodinated amiodarone analogue, fewer thyroid/lung effects but contraindicated in NYHA III–IV / decompensated HF and permanent AF (ANDROMEDA, PALLAS trials → ↑mortality).
• Sotalol: non-selective β-blocker + K⁺ block → ↑QT, dose-dependent torsades risk; monitor QT and renal function.
• Dofetilide / Ibutilide: pure I_Kr blockers for AF conversion; significant torsades risk — ibutilide is the highest torsades-risk drug, used for chemical cardioversion of recent AF/flutter under monitoring.

Class IV — calcium-channel blockers

Non-dihydropyridines verapamil and diltiazem slow AV nodal conduction → rate control in AF/flutter and termination of AV-nodal re-entrant SVT.

High-yield: Verapamil/diltiazem are contraindicated in WPW with AF — blocking the AV node diverts conduction down the fast accessory pathway → very rapid ventricular rate → VF. Same caution for digoxin and adenosine in pre-excited AF.

"Unclassified" agents

• Adenosine: activates A1 receptor → opens K⁺ (I_KACh) channels + inhibits adenylyl cyclase → transient complete AV block. DOC for acute termination of paroxysmal SVT (AVNRT/AVRT). Ultra-short t½ (<10 s). Give rapid IV push + saline flush. Side effects: flushing, chest tightness, transient asystole, bronchospasm. Theophylline/caffeine antagonise it; dipyridamole potentiates it.
• Digoxin: vagomimetic ↑AV refractoriness — rate control in AF, especially with HF; poor for exercise rates.
• Magnesium sulphate: DOC for torsades de pointes and digoxin-induced arrhythmias.
• Ivabradine: selective I_f (funny channel) blocker — lowers SA rate without affecting BP/contractility; used in inappropriate sinus tachycardia and HFrEF.
• Atropine: DOC for symptomatic bradycardia/AV block.

Drug of choice — the money table

Arrhythmia	Acute DOC	Notes
Paroxysmal SVT (AVNRT/AVRT)	Adenosine (after vagal manoeuvres)	Verapamil if adenosine fails
AF — rate control	β-blocker / diltiazem / verapamil	Digoxin if HF
AF — rhythm control	Amiodarone, flecainide/propafenone (no structural disease), ibutilide
Atrial flutter	Catheter ablation (definitive); ibutilide/rate control acutely
WPW with AF (pre-excited, wide irregular)	Procainamide / ibutilide; DC shock if unstable	Avoid AV-nodal blockers
Stable monomorphic VT	Amiodarone (or procainamide)
Pulseless VT / VF	Defibrillation + adrenaline + amiodarone	Lidocaine alternative
Torsades de pointes	IV Magnesium, correct K⁺/Mg, overdrive pacing	Stop offending drug
Digoxin toxicity arrhythmia	Digoxin-specific Fab (Digibind) + phenytoin/lidocaine + Mg
Symptomatic bradycardia	Atropine → transcutaneous pacing

Acute narrow-complex SVT flow: Vagal manoeuvres → Adenosine 6 mg IV push → 12 mg → 12 mg → if unstable at any point → synchronised DC cardioversion.

Proarrhythmia — a tested paradox

Antiarrhythmics can cause arrhythmias:

• IA & III → QT prolongation → torsades de pointes (early afterdepolarisations).
• IC → incessant VT, ↑mortality in ischaemia (CAST).
• Digoxin → delayed afterdepolarisations → bidirectional VT.

High-yield: Bidirectional VT is the classic ECG of digoxin toxicity (also aconite poisoning, CPVT).

Key drug interactions & monitoring

• Amiodarone ↑ warfarin (bleeding) and ↑ digoxin → halve digoxin dose.
• Quinidine ↑ digoxin (displaces from tissue + ↓renal clearance).
• Hypokalaemia/hypomagnesaemia potentiate torsades — always correct electrolytes.
• Sotalol/dofetilide need QTc and creatinine monitoring; renally excreted.

Recently asked / exam angle

• MOA matching: "Drug that blocks I_Kr / prolongs phase 3" → Class III; "funny channel blocker" → ivabradine.
• Amiodarone toxicity image/clinical vignettes — slate-grey skin, fibrosis on CXR, abnormal TFTs.
• CAST trial linked to flecainide contraindication post-MI.
• DOC for SVT (adenosine) and DOC for torsades (Mg) are repeat single-best-answer favourites.
• WPW + AF → avoid verapamil/digoxin/adenosine (mechanism-based question).
• Procainamide → drug-induced lupus (anti-histone Ab).
• Disopyramide negative inotropy / used in HOCM.
• Lidocaine ineffective in atrial arrhythmias (use-dependence reasoning).
• Bidirectional VT = digoxin toxicity.
• Esmolol pharmacokinetics (esterase metabolism, short t½) in perioperative tachycardia.

Rapid revision

1. Singh-Vaughan-Williams: I Na⁺, II β-block, III K⁺, IV Ca²⁺ — plus adenosine/digoxin/Mg unclassified.
2. IA lengthens APD, IB shortens, IC unchanged ("A apart, B brief, C same").
3. QT-prolonging classes = IA + III → torsades risk.
4. Adenosine = DOC for acute PSVT; antagonised by theophylline/caffeine.
5. Magnesium = DOC for torsades de pointes.
6. Amiodarone = pulmonary fibrosis + corneal deposits + thyroid dysfunction; raises warfarin & digoxin.
7. Lidocaine works on ventricle (ischaemic tissue), useless for atria.
8. Flecainide (IC) contraindicated post-MI / structural heart disease — CAST trial.
9. Verapamil/diltiazem/digoxin/adenosine contraindicated in WPW with AF.
10. Procainamide → drug-induced SLE (anti-histone); disopyramide → most negative inotrope, anticholinergic.
11. Bidirectional VT = digoxin toxicity; treat with Digoxin-Fab.
12. SA/AV nodes are Ca²⁺-dependent → β-blockers and CCBs slow them.