Antiarrhythmic drugs can be classified according to their mechanism of action. Therefore, the Vaughan-William classification discriminates five groups:
The class 1 constitutes the sodium channel blockers and is, in turn, divided into three groups (1A, 1B and 1C), based on the action potential duration, the amount of reduction of the phase 0 slope, and effective refractory period.
The class 2 drugs constitute of beta blockers and class 3 are potassium channel blockers – amiodarone, dronedarone, bretylium, sotalol, ibutilide and dofetilide. These will be discussed in this article.
Calcium channel blockers are classified as group 4 and miscellaneous drugs are class 5.
Mechanism of Action of Potassium Channel Blockers
Potassium is the chief ion in the repolarisation. At the end of depolarisation, potassium efflux occurs following the opening of the potassium channels. This takes place until the next action potential stimulus occurs, where the impulse above the threshold level required for the depolarisation has occurred.
These group of drugs bind to the channel which is responsible for the potassium movement and blocks it (rapid component of the delayed rectifier current (IKr)). Once the blocking has happened, the refractory period increases.
The refractory period is further divided into two types, named relative and absolute refractory period. The potassium channel blocker increases the duration of the absolute refractory period of both the atria and the ventricle; thus the action potential widens.
One of the important mechanisms which cause continuous tachyarrhythmia is the circuit of excitatory impulse which excites the ventricle again and again. The potassium channel blocker blocks these re-entry circuits by means of inhibition of the effect of the impulse by making the tissue refractory by the time the impulse arrives.
It is worth to note that the amiodarone is said to have an electrophysiological property in addition to its potassium channel blocking property. It also acts as a sodium channel blocker, anti-adrenergic and L -type calcium channel blocker (note that these are the property of the class 1, class 3 and class 4 drugs according to the Vaughan-Williams classification respectively).
All these are the reason behind the therapeutic efficacy of amiodarone.
Amiodarone has shown efficacy in the management of both supraventricular and ventricular arrhythmias, but its approved usage is limited by its long time for the onset of action and its array of side effects.
Pros & Cons and the Main Indication of Amiodarone
For easy understanding, the indication can be taken, that the amiodarone both IV and oral are given as a maintenance treatment, restoration treatment and for the prophylaxis for the prevention of occurrence of atrial fibrillation.
Though not FDA approved, the oral amiodarone is widely used for the maintenance treatment of the sinus rhythm in patients with atrial fibrillation. Though oral amiodarone is not a recommended therapy for the cardioversion in active atrial fibrillation (this is because the oral amiodarone takes time for its action to occur), it can be given in some cases.
The oral amiodarone is also used for the prevention of paroxysmal atrial fibrillation. The intravenous amiodarone is used mainly in severe cases and the indications include the maintenance of sinus rhythm in AF patients who are unstable hemodynamically.
Though convincing evidence is not available, amiodarone is used for the restoration of sinus rhythm in patients with unstable atrial fibrillation. The critical ill patient forms the main treatment group (in these groups of patients, ventricular fibrillation occurs along with atrial fibrillation contributing to the unstability).
Given as a Prophylaxis
Amiodarone (both oral and intravenous) is used as a prophylaxis before cardiac surgery in order to prevent atrial fibrillation in high-risk patients. The drug is also given to those patients who have high risk of atrial fibrillation during electrical cardioversion. The treatment in this case should start long before (2-6 weeks before the planned cardioversion).
Oral amiodarone has shown efficacy in preventing the occurrence of VT in patients with myocardial infarction and congestive heart failure.
Ventricular Refractory Arrhythmia and Pulseless VT and VF (Sudden Cardiac Death)
A recent RCT (2016) published in NEJM, where the lidocaine, amiodarone and placebo are compared for the pulseless VT or VF in those patients in whom the initial defibrillation or vasopressor therapy has shown refraction, has shown that there is no difference in the survival (primary outcome of the trial).
There occurred a mild non-significant survival benefit on both the drug treatment groups when compared to the placebo in the bystander witnessed arrest.
It has to be noted that the two most famous trials, namely the ALIVE trial and the ARREST trial, where amiodarone has been compared with lidocaine in sudden cardiac arrest patients having persistent VF even after the defibrillation shock, have shown only the improvement in the rate of hospital admission after the arrest.
In the same trial, there was no significant benefit in the survival of the patient. In the ARREST trial, amiodarone was associated with more side effects.
Based on the above evidences, amiodarone is suggested by the AHA guidelines as the first line drug for the treatment during sudden cardiac arrest, rather than lidocaine (this is also confirmed by a Cochrane study).
It should, however, be remembered that the first line of therapy to be given to a patient with VF or VT related sudden cardiac arrest is the effective CPR along with defibrillation, if indicated.
The defibrillation (implantable cardioverter-defibrillators (ICDs)) is the only proven effective treatment of the VF and VT. The administration of the antiarrhythmic drugs, like amiodarone and lidocaine, is only after trying with the CPR and defibrillator.
Pharmacokinetics of Amiodarone
The oral amiodarone is lipophilic and takes times to attain the intended concentration in the blood (due to the increase in the volume of distribution seen with the lipophilic drugs).
Amiodarone is an inhibitor of CYP3A4, so the interaction concerned with the drugs which get metabolized by the CYP3A4 needs to be taken care of.
The drug also significantly interacts with the warfarin requiring dose modification. In addition to this, the alteration in the thyroid function, caused by the amiodarone, further affects the warfarin concentration.
Adverse and Side Effects Related to Amiodarone
Though amiodarone is almost a wonder drug in arrhythmias, it has gone into disfavour mainly because of its side effect profile. That’s the reason why it is used mainly in the refractory ventricular arrhythmia, rather than the atrial fibrillation even in which it has high efficacy.
The side effects are mainly seen with long term therapy, rather than short term intravenous therapy.
The exposure to even a low dose of oral amiodarone for a long duration has the following odds of developing side effects when compared to the placebo namely 4.2, 3.4, 2.0 for thyroid, ocular and skin/neurological/pulmonary toxicity respectively. The above data is according to a meta-analysis on the side effect profile (5).
The side effect profile of the oral and intravenous amiodarone is different. The most common adverse effect with the intravenous preparation is hypotension, and this is significantly reduced by the latest pharmaceutical preparation (containing aqueous base).
It should be noted that although the amiodarone is more potent than compared to another group of antiarrhythmic agents, the rate of proarrhythmic effect is impartiality less. When the arrhythmia occurs with amiodarone, the most common seen is the Torsades de pointes. The risk increases in women and with the presence of other co-electrolyte abnormality.
The most common cause of death with a patient on amiodarone therapy is pulmonary toxicity with the most important predictor being the cumulative dose given. The most common type of pulmonary toxicity involves chronic interstitial pneumonitis and the presence of an increased number of foamy macrophages in the lungs’ air spaces.
This warrants immediate stoppage of the drug and the treatment with the corticosteroid for the patient.
The other side effects include gastrointestinal disturbances, liver function abnormalities, bradycardia, asystole, localised phlebitis, non-productive cough, acute respiratory distress syndrome (rare), and bluish-slate gray discoloration of the skin, along with the presence of photosensitivity.
In addition, neurological toxicity, like peripheral neuropathy, paraesthesia, abnormal walking, and alteration in the lipid level in the blood, are seen. There occurs a possibility of both hypothyroidism, as well as hyperthyroidism, with the treatment with amiodarone.
There occurs reversible corneal deposit in the patients in the treatment with amiodarone. As the vision remains still intact, the corneal micro deposits are not an indication for stopping the amiodarone therapy. The mechanism behind the formation is due to the secretion of the amiodarone through the lacrimal gland. There also occurs the risk of optic nerve injury causing blindness.
Regarding the liver function abnormality, it is recommended to monitor the liver function for every 6 months for the patients in the treatment with amiodarone. Secondly, the drug needs to be discontinued if the elevation in the liver enzyme is more than the two fold elevation.
The two proposed mechanisms are phospholipidosis (the phospholipid of the liver interacts with the amiodarone) and metabolic idiosyncrasy (potential of some individual to produce more toxic metabolites from a given drug).
Reverse Use Dependence
Except for the amiodarone, all the other members of the class 3 antiarrhythmic drugs, like sotalol, exert the property of reverse use dependence. This means that, as the heart rate decreases, there occurs an increased risk of prolongation of QT interval. This increases the risk of Torsades de pointes and also decreases the efficacy of the drug.
There are also other proposed mechanisms on why the incidence of Torsades de pointes is less with amiodarone; they include the properties of amiodarone like concurrent inhibition of the L type calcium channel, but still it is not fully understood.
The mechanism of action is the same as of the whole group. It acts on all the 4 channels (sodium, potassium, calcium and the alpha 1 and it antagonizes all these receptors).
The drug is used in those patients with persistent AF, who need to reduce the risk of hospitalization for AF (note, in these patients the rhythm can still be reverted back). The drug is also used for the treatment of AF in patients of HOCM.
The drug is contraindicated in patients with NYHA class 4 symptomatic heart failure. Dronedarone is also shown to increase the risk of death in those patients with permanent atrial fibrillation whose rhythm can never be reverted back, so it is contraindicated in patients with permanent AF.
Prolonged QT is the most common adverse effect seen with this drug. Along with that, there occurs an increase in the renal parameters, dermatologic manifestation like allergic dermatitis, neuromuscular weakness and bradycardia.
The drug is a racemic mixture of d and l isomers. The concentrations of both the isomer are in approx. 1:1 concentration and have a different mechanism of action.
The d isomer has the blocking property of the delayed rectifier potassium channel (similar to other drugs in the class 3 antiarrhythmics); the l isomer in addition to this property also has a beta blocking property.
It should be noted that although the name sotalol sounds like a beta blocker, it is classified under the class 3 anti-arrhythmic agent based on its functional properties.
Oral sotalol is used for the treatment of sustained VT which is potentially life threatening and in currently sinus rhythm patients who have the risk of developing atrial fibrillation.
The drug should not be given in patients with congenital long QT prolongation and the common side effects which are seen are a decrease in the heart rate, difficulty in breathing, a dizzy feeling, fatigue and a lack of energy feeling.