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PH4.10 | PH4.10 | Antiarrhythmic Drugs — SDL Guide (Part 2)

Class I and Class II Antiarrhythmics: PK, PD, Uses, ADRs

Class Ia agents (quinidine, procainamide, disopyramide) are the oldest antiarrhythmic drugs and are now largely superseded by safer alternatives. They block fast Na channels with intermediate rate-of-recovery kinetics AND block IKr (a potassium channel) → prolong the action potential duration → widened QRS + prolonged QT interval. The QT prolongation risk, combined with the vagolytic effects of quinidine (which can cause reflex tachycardia and paradoxically precipitate TdP), has severely limited their clinical use. Quinidine cinchonism (tinnitus, hearing loss, diarrhoea, thrombocytopenia); procainamide → drug-induced lupus with chronic use (anti-histone antibodies, arthralgia, rash — more common in slow acetylators, similar to hydralazine).

Class Ib agents (lidocaine, mexiletine) have fast dissociation kinetics and preferentially block Na channels in depolarised (ischaemic) tissue — showing very little effect on normally polarised myocardium. This use-dependent selectivity for ischaemic tissue makes lidocaine ideal for ventricular arrhythmias complicating acute MI without affecting normal conduction. Lidocaine IV (1–1.5 mg/kg bolus) is second-line (after amiodarone) for pulseless VT/VF in the ALS algorithm and for haemodynamically stable VT in the context of acute MI. It does NOT prolong QT. Lidocaine has essentially no oral bioavailability (>90% first-pass liver metabolism) — IV only. Mexiletine is the oral analogue used for chronic VT management.

Class Ic agents (flecainide, propafenone) are the most potent Na-channel blockers — slow dissociation kinetics mean they remain bound to Na channels for the entire cardiac cycle at faster heart rates (use-dependent block), producing significant QRS widening. Flecainide is highly effective for AF rhythm control in patients with structurally normal hearts — it converts AF to sinus rhythm and prevents recurrence. The critical prescribing constraint is the CAST trial (1989): in post-MI patients, even asymptomatic, flecainide INCREASES mortality by creating a substrate for re-entrant VT in ischaemic tissue. Absolute contraindication: structural heart disease, post-MI, LV dysfunction (EF <40%). Always check LV function before prescribing flecainide.

Class II agents (beta-blockers): Propranolol (non-selective), metoprolol, atenolol, bisoprolol reduce catecholamine-driven automaticity in the SA node (slows sinus rate) and slow AV nodal conduction (reduces ventricular rate in AF and SVT). They are the first-line rate-control drugs for AF and the first-line choice for SVT prevention (as oral prophylaxis after adenosine terminates the acute episode). They are the only antiarrhythmics with proven post-MI mortality reduction. Adverse effects in arrhythmia use: bradycardia, AV block, worsening bronchospasm (non-selective agents — avoid in asthma/COPD), fatigue, impotence, hypoglycaemia masking.

Class III, Class IV, Adenosine, and Digoxin: PK, PD, Uses, ADRs

Amiodarone is the most effective antiarrhythmic drug available and is unique in possessing actions from ALL FOUR Vaughan-Williams classes:
- Class I (Na-channel block): ↓conduction velocity
- Class II (beta-blocker effect): ↓SA node automaticity, ↓AV conduction
- Class III (K-channel block, IKr): ↑APD, ↑refractoriness, prevents re-entry
- Class IV (Ca-channel block): additional AV nodal slowing
This 'pan-channel' mechanism makes amiodarone effective for nearly all tachyarrhythmias: AF conversion and maintenance, VT, VF. It is the first-line IV antiarrhythmic in the ALS cardiac arrest algorithm for shock-refractory VF (300 mg IV bolus).

The clinical challenge with amiodarone is its extraordinary pharmacokinetic profile and toxicity burden:
PK: highly lipophilic; accumulates in adipose tissue, lung, liver, thyroid; plasma half-life 40–55 days (the longest of any cardiac drug). Loading is required (oral: 200 mg TDS for 1 week, then 200 mg BD for 1 week, then 200 mg OD maintenance; IV: 300 mg loading, then infusion). Drug interactions are extensive: amiodarone inhibits CYP2C9 (→ ↑warfarin — INR doubles, reduce warfarin dose by 25–30%) and CYP3A4 (→ ↑statins, ↑digoxin — monitor levels).
ADRs (require monitoring for long-term use):
1. Pulmonary toxicity: pulmonary fibrosis/alveolitis in 5–10% on chronic therapy; monitor with annual CXR/PFTs; can be fatal; requires drug discontinuation.
2. Thyroid dysfunction: both hypothyroidism and hyperthyroidism (iodine-rich molecule; interferes with thyroid hormone synthesis AND metabolism); check TFTs 6-monthly.
3. Hepatotoxicity: raised transaminases; rarely hepatic fibrosis; check LFTs 6-monthly.
4. Corneal microdeposits: nearly universal with long-term use; rarely affect vision; irreversible but usually asymptomatic; slit-lamp monitoring recommended.
5. Photosensitivity and blue-grey skin discolouration: from iodine deposition.
6. Peripheral neuropathy: uncommon but important.
7. QT prolongation: despite being Class III, amiodarone paradoxically causes less TdP than other Class III agents (sotalol, dofetilide) — possibly due to its multi-class actions reducing the conditions that allow TdP.

Sotalol is a Class III agent (IKr block → ↑APD → ↑QT) with additional Class II (beta-blocker) effects. Used for AF rhythm control and VT prevention. The QT-prolonging effect requires that serum K and Mg are normal before initiation, and QT monitoring is mandatory. Dose titration should be in-hospital due to TdP risk, especially in hypokalaemic patients and those with renal impairment (sotalol is renally cleared).

Class IV (non-dihydropyridine CCBs — verapamil, diltiazem): Block L-type Ca channels in the SA and AV nodes → slow AV conduction → rate control in AF and termination of AV-node-dependent SVT. IV verapamil terminates AVNRT effectively. Key contraindications:
- Combination with beta-blockers: both agents slow AV conduction → synergistic risk of complete AV block and severe bradycardia — avoid this combination.
- WPW + AF: verapamil blocks AV node → all impulses must go through the accessory pathway → very rapid ventricular pre-excitation → VF. Verapamil is ABSOLUTELY CONTRAINDICATED in AF with WPW syndrome. (Digoxin has the same hazard — it also preferentially slows AV nodal conduction.)
- HFrEF: verapamil and diltiazem are negative inotropes — contraindicated.

Adenosine: Rapid IV bolus (6 mg, followed by 20 mL saline flush; repeat with 12 mg if unsuccessful). Half-life approximately 10 seconds — metabolised in red blood cells by adenosine deaminase. Mechanism: A1 receptor activation → ↑K conductance (IKAch) → hyperpolarises AV nodal cells → transient complete AV block lasting 10–30 seconds → interrupts AV-node-dependent re-entry (AVNRT, orthodromic AVRT) → sinus rhythm. Causes transient side effects: chest tightness (almost universal), facial flushing, dyspnoea (brief). Contraindicated in severe asthma (bronchospasm). In WPW with AF: adenosine is generally AVOIDED because it slows the AV node without affecting the accessory pathway — may increase the relative contribution of pre-excited conduction → accelerate accessory pathway → VF risk.

Digoxin as antiarrhythmic: Acts via vagal stimulation + mild direct Na-K-ATPase inhibition at the AV node → slows ventricular rate in AF (rate control adjunct). Less effective than beta-blockers at rate control during exercise (vagal effect diminishes with sympathetic activation). Useful in AF + HFrEF (where beta-blockers may need lower doses). Narrow therapeutic index — monitor levels (0.5–0.9 ng/mL) and potassium (hypokalaemia potentiates toxicity — covered in cvs1-heart-failure SDL).

Clinical Decision-Making: SVT, AF, Ventricular Arrhythmias, and Cardiac Arrest

Arrhythmia-specific drug selection is the essential clinical skill in antiarrhythmic pharmacology. The following frameworks provide decision guidance for the four most clinically important arrhythmia categories.

Supraventricular tachycardia (SVT — specifically AVNRT, AVRT):
- Acute termination: vagal manoeuvres first (Valsalva, carotid sinus massage) → if unsuccessful, IV adenosine 6 mg (most SVTs are AV-node-dependent and terminate with transient AV block). If adenosine fails: IV verapamil or IV diltiazem (for patients WITHOUT WPW or pre-excitation). Avoid verapamil in WPW.
- Recurrence prevention: oral beta-blocker (atenolol, metoprolol) or oral verapamil/diltiazem (not in HFrEF); radiofrequency ablation for definitive cure.

Atrial fibrillation (AF):
- Rate control (most patients with persistent/permanent AF): oral beta-blocker (metoprolol, bisoprolol) first-line; OR non-DHP CCB (verapamil, diltiazem) if beta-blockers contraindicated; digoxin added if HR remains uncontrolled or in HFrEF. Target resting HR <80–100 bpm.
- Rhythm control (paroxysmal AF, recent-onset, haemodynamic compromise, younger patients): electrical cardioversion or pharmacological cardioversion with IV flecainide (if no structural heart disease) or IV ibutilide; THEN maintain sinus rhythm with: amiodarone (most effective; used if HFrEF or structural heart disease), flecainide (structurally normal heart only), sotalol (in hospital initiation, K monitoring), or propafenone.
- Anticoagulation: All AF patients (paroxysmal, persistent, or permanent) with CHA₂DS₂-VASc ≥2 (men) or ≥3 (women) require anticoagulation (DOAC preferred over warfarin) to prevent AF-associated stroke — this is independent of the rate vs rhythm control strategy.

Ventricular tachycardia (VT) — haemodynamically stable:
- Pulseless/haemodynamically unstable: DC cardioversion (synchronised) immediately.
- Haemodynamically stable monomorphic VT: IV amiodarone 150–300 mg over 10 min (first choice); IV lidocaine (especially in acute MI); IV procainamide. Assess and treat underlying ischaemia.
- Long-term prevention: oral amiodarone; sotalol; ICD (superior to drugs for secondary prevention — AVID trial).

Cardiac arrest (VF or pulseless VT):
- Basic + Advanced Life Support: CPR + defibrillation first (ONLY definitive treatment for VF).
- After third shock, if VF persists: IV amiodarone 300 mg bolus (first-line in ALS algorithm); lidocaine 1 mg/kg IV (alternative if amiodarone unavailable); adrenaline (epinephrine) 1 mg IV every 3–5 min (vasopressor to maintain coronary perfusion pressure, not an antiarrhythmic).

Torsades de pointes (TdP) management:
- Stop the offending QT-prolonging drug (Class Ia, Class III, also many non-cardiac drugs: azithromycin, haloperidol, domperidone).
- Correct precipitating factors: hypokalaemia (IV KCl), hypomagnesaemia.
- IV MgSO4 2 g over 10–15 minutes — first-line treatment (stabilises membrane, shortens QT).
- If recurrent: cardiac pacing (overdrive pacing at 100 bpm shortens QT and prevents EAD triggering).

Self-Assessment: Antiarrhythmic Drug Selection

Consolidate your understanding with the following reference summaries.

Vaughan-Williams classification quick reference:

Class	Mechanism	Examples	Key indication	Key ADR/caution
Ia	Na-channel block (intermediate) + K block → ↑QT	Quinidine, procainamide, disopyramide	AF (historical), VT	TdP, drug-induced lupus (procainamide)
Ib	Na-channel block (fast) — depolarised tissue only	Lidocaine, mexiletine	Acute MI VT (IV lidocaine)	CNS toxicity (tremor, seizures at high doses)
Ic	Na-channel block (slow) — potent	Flecainide, propafenone	AF (structurally normal heart)	CONTRAINDICATED post-MI/structural HD (CAST)
II	Beta-adrenergic block	Propranolol, metoprolol, bisoprolol	SVT rate control, AF rate control, VT post-MI	Bradycardia, AV block, bronchospasm
III	K-channel block (↑APD/QT)	Amiodarone (+ I/II/IV), sotalol (+ II), dofetilide	AF (amiodarone all; flecainide contraindicated with HD); VF (amiodarone)	QT prolongation, TdP (sotalol>>amiodarone); amiodarone: pulmonary/thyroid/hepatic toxicity
IV	L-type Ca-channel block (nodal)	Verapamil, diltiazem	SVT termination/prevention, AF rate control	Contraindicated in HFrEF, WPW+AF, with beta-blockers

Hazardous drug combinations in arrhythmias:
- Non-DHP CCB + beta-blocker → complete AV block (avoid)
- Class Ic + structural heart disease → pro-arrhythmic death (CAST lesson)
- Amiodarone + warfarin → ↑INR (CYP2C9 inhibition; reduce warfarin dose)
- Any QT-prolonging drug + hypokalaemia → TdP
- Verapamil/digoxin/adenosine + WPW + AF → VF (absolutely avoid)