Class III

• The Important agents in this class; Amiodarone, Dronedarone, Sotalol, Vernakalant, Ibutilide

• Class III agents predominantly block the potassium channels, thereby prolonging repolarization and prolonging the refractory period.

• Since class III do not affect the sodium channel, conduction velocity is not decreased significantly. The prolongation of the action potential duration and refractory period, combined with the maintenance of normal conduction velocity, prevent re-entrant arrhythmias. Because the re-entrant rhythm is less likely to interact with tissue that has become refractory. (Notice that some of these agents have also other classes functions, thereby they could effect on conduction velocity.)

Amiodarone

• Multichannel blocker with antiadrenergic properties → So ↑ RR, PR, QRS, and QT

• It can be used to treat supraventricular and ventricular tachyarrhythmias and has the added advantage of being well tolerated in patients with impaired left ventricular systolic function with a low incidence of arrhythmic events, such as torsades de pointes.

• We use Amiodarone in emergency and CCU frequently. So after treatment of acute phase of arrhythmia, Amiodarone is not the first choice, because of extreme risk of extracardiac side effects.

• Owing to its marked lipid affinity, it is highly concentrated in tissues and is linked to a number of adverse effects, including thyroid dysfunction. Amiodarone can lead to both hypothyroidism and less commonly hyperthyroidism and relates to high iodine content within the molecule as well as to several unique intrinsic properties of amiodarone.

• Laboratory follow up at starting, 3 months, 6 months and then every year → Electrolytes & creatinine, ECG, Thyroid-tests (TSH, T4V), Liver-test (ALAT)

• half-life 45 days

• Pulmonary fibrosis → fatal in 10% → At starting chest-xray and spirometry with diffusing capacity → Also later in follow up, if there are sign or symptom.

• Major cardiovascular side effect → bradycardia

• Marked QT prolongation can occur, but it is very rarely associated with torsades de pointes. (Kirchhof P...et al. J Am Coll Cardiol. 2009)

• In patients with LV hypertrophy, HF, CAD, and/or previous MI, amiodarone is associated with a low risk of proarrhythmia, making it an appropriate initial choice to prevent recurrent AF in these clinical settings. AHA/ACC/HRS Guideline 2014

Sotalol

• Sotalol induces beta-blockade in low dosage and exerts class III anti-arrhythmic effects in high dosage (prolongation of repolarization by blocking potassium channels).

• In SAFE Trial, the efficacy of sotalol to maintain sinus rhythm was not inferior to amiodarone in the subgroup of patients with ischaemic heart disease.

• Proarrhythmia; Prolongation of the QT interval or bradycardia → QT interval 500 ms → Sotalol should be stopped or the dose reduced. European Heart Journal (2010), ESC guideline

• Women, and patients with marked LVH, severe bradycardia, ventricular arrhythmias, renal dysfunction, or with hypokalaemia or magnesaemia are at increased risk of proarrhythmia. European Heart Journal (2010), ESC guideline

• During follow-up, serum potassium and magnesium levels and renal function should be checked periodically. Some experts initiate sotalol in hospital. AHA/ACC/HRS Guideline 2014

• According to the SWORD trial, the class III effect (as exerted by d-sotalol) seems to be associated with increased mortality in patients with severely reduced systolic pump function (EF = 40%) after myocardial infarction. (Waldo AL,...VeltriEP. Effect of d-sotalol on mortality in patients with left ventricular dysfunction after recent and remote myocardial infarction.  Lancet 1996;348:7-12. )

• In a retrospective analysis derived from 22 clinical trials involving 3135 adult patients who received oral d, l-sotalol, a history of CHF was one of the factors most predictive of torsade de pointes ventricular tachyarrhythmia. (Lehmann MH,...,MacNeil DJ. Sex difference in risk of torsade de pointes with d,l-sotalol. Circulation 1996;94:2535-2541.) → Therefore, d, l-sotalol should be avoided in patients with CHF.

Dronedarone

• It was approved by the FDA on 2009. It was recommended as an alternative to amiodarone for the treatment of atrial fibrillation and atrial flutter as a rhythm control agent. Dronedarone (Multaq) less effective but safer than amiodarone.

• Its multiple electrophysiological actions include sympatholytic effects as well as blocking of calcium, sodium, and potassium currents.

• Increases mortality in patients with recently decompensated HF and depressed LV function (Kober L...et al. N Engl J. 2008) → It is contraindicated in patients with NYHA class III HF, episode of decompensated HF in the past 4 weeks.

• Dronedarone can be administered with verapamil or diltiazem, but low doses of these agents should be used initially and titrated according to response and tolerance. AHA/ACC/HRS Guideline 2014

• In patients with permanent AF, dronedarone increases the combined endpoint of stroke, cardiovascular death, and hospitalization (Connolly SJ...et al. N Engl J. 2011) → It is contraindicated in patients whose sinus rhythm is not restored. AHA/ACC/HRS Guideline 2014

Vernakalant

• It is a i.v. drug for the acute conversion of atrial fibrillation. Vernakalant can be given to patients withmild heart failure (NYHAClass I or II), including those with ischaemic heart disease, provided they do not present with hypotension or severe aortic stenosis. (ESC AF guidelines 2016)

Vernakalant blocks atrial potassium channels, thereby prolonging repolarization. The drug also blocks atrial sodium channels.

• It differs from typical class III agents by blocking a certain type of potassium channel.

• It is more effective at high heart rates. It's mainly used for rapid conversion of acute-onset AF (AF lasting 3 to 72 hours).

 

 

Compilation by Dr. Samad Ali Moradi, According to Finnish cardiology references & author work experience.