Pharmacology of major drug classes used - antiarrhythmic drugs

Classification

Class	Target	Agents	Main use
Ia	Na+ (intermediate), inc APD	Quinidine, procainamide, disopyramide	Largely historical; disopyramide in HOCM
Ib	Na+ (fast on-off)	Lidocaine, mexiletine	Ventricular only
Ic	Na+ (slow on-off, use-dependent)	Flecainide, propafenone	AF/SVT in structurally normal hearts
II	Beta-adrenergic	Metoprolol, bisoprolol, esmolol	Rate control, post-MI, HF
III	K+ (IKr), inc APD	Amiodarone, sotalol, dronedarone	AF, VT
IV	L-type Ca2+	Verapamil, diltiazem	Rate control, fascicular VT
Other	-	Digoxin, adenosine, magnesium, ivabradine	-

Class I and III act on myocytes and His-Purkinje; class II and IV on SA/AV nodal pacemaker cells
*CAST: suppressing ectopy with class Ic post-MI increased mortality*

Amiodarone is the most used and the most toxic - the trade-off defines the class
Antiarrhythmic drugs roughly halve AF recurrence versus placebo; none abolishes it

Potent use-dependent Na channel block
- -> dec conduction velocity
- -> prolonged refractoriness in atria, His-Purkinje, ventricle and accessory pathways
Slows atrial rate -> AF becomes slow flutter -> 1:1 AV conduction at 200+. Always co-prescribe an AV nodal blocker
Contraindicated in structural heart disease and IHD

IKr block + non-selective beta blockade
- -> inc action potential duration in atria and ventricles
- -> dec sinus rate and AV conduction
QT prolongation -> torsades

Properties of all four Vaughan Williams classes; classified III by convention
IV: acute Na and Ca current inhibition plus anti-adrenergic effect
Least proarrhythmic, most organ-toxic

QTc before and after starting any class III agent
Sotalol - renal function (renally cleared), K+, Mg2+, ECG at steady state
Flecainide - exclude structural disease with echo +/- ischaemia assessment before starting
Amiodarone - baseline then 6-monthly TFTs, LFTs, UEC; baseline CXR and DLCO; annual eye review
Digoxin - trough level (>=6 h post-dose), K+, Mg2+, renal function

Structurally normal heart - flecainide (with an AV nodal blocker) or sotalol
Structural heart disease or HF - amiodarone
Dronedarone contraindicated in permanent AF and in heart failure

Amiodarone for acute treatment and prophylaxis; lidocaine an alternative in ischaemic VT
Beta blockers reduce mortality
*No antiarrhythmic drug prevents sudden death - an ICD does*
Torsades: IV magnesium, correct K+, stop the offending drug, overdrive pacing

Adenosine to terminate; verapamil or diltiazem; flecainide or ablation for prevention

Contraindicated: 2nd/3rd degree block, WPW, acute MI, VT/VF, HOCM
Toxicity
- Bradycardia, ectopy, bigeminy, junctional rhythm, AV block, VT
- Hyperkalaemia - degree correlates with mortality
- Yellow halos, confusion, lethargy, nausea and vomiting
- ECG: scooped ST segments, flat or inverted T waves
- Precipitated by hypokalaemia, hypomagnesaemia, hypercalcaemia, renal impairment
- Hypothyroidism raises levels; hyperthyroidism lowers them
- Digoxin-specific Fab for significant toxicity

Amiodarone interactions - raises digoxin and warfarin levels
- Halve the digoxin dose and recheck the INR
QT-prolonging combinations - macrolides, quinolones, azoles, antipsychotics, ondansetron, methadone
Verapamil or diltiazem with a beta blocker - additive negative chronotropy
Renal impairment - sotalol and digoxin both accumulate

Every antiarrhythmic is proarrhythmic - this is the organising principle of the class
- Class Ic: incessant VT, 1:1 atrial flutter, excess mortality post-MI (CAST)
- Class III: torsades de pointes

Amiodarone organ toxicity - dose- and duration-dependent

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