Amiodarone

The Discovery of Amiodarone

Anisa Moore

24 September 2018

Amiodarone and bretylium are both antiarrhythmic agents with labeled indications for

ventricular arrhythmias (LexiComp). Amiodarone was developed from a flowering plant called

khella while, bretylium was discovered examining the relationship of substituted phenylcholine

ethers (Ammi visnaga and Green).

Bretylium works by prolonging the duration of the action potential and effective

refractory period in Purkinje fibers and ventricular tissues and inhibiting norepinephrine release

by reducing adrenergic nerve terminal excitability (Lexicomp). This medication was discovered

in the 1950s through the examination of a series of phenylcholine ethers. Out of the compounds,

bretylium was selected for clinical trials because of its minimal cholinergic effects (Green). In

the 1960s, however, the use of bretylium was questioned due to the undesirable effects that

included dizziness, increased frequency of micturition, muscle weakness, and parotid pain

(Green). It was thought that these adverse effects could be tolerable, but it would be ideal for the

medication to be more effective. Patients taking bertylium were also developing a tolerance to

the medication and this tolerance could not always be overcome with higher doses of the drug.

Because of these reasons, other antiarrhythmic medications, like amiodarone, from the khella

plant, are more commonly used (Green).

Khella, or Ammi visnaga, is a plant commonly found in Egypt, other regions in the

Middle East, and the Mediterranean. The khella plant has been used in traditional medicine for

millennia for treatments of disease states including kidney and bladder stones, diabetes, and

urinary tract infections (Ammi visnaga). Scientists were able to identify the positive

cardiovascular effects of this plant when high extracts, called khellin, were effective in the

reduction of angina in patients that were using it for other purposes. This discovery resulted in

the synthesis of amiodarone from khella (Ammi visnaga).

Amiodarone was synthesized in 1961 by a chemist from Belgium who was working on

compounds derived from khellin. Amiodarone became widely used in Europe by 1980 and was

then approved in the United States in 1985 (Marraffe). Amiodarone’s primary mechanism of

action is potassium channel blocking, but it also works by sodium channel blocking, inhibiting

adrenergic stimulation through nonselective alpha- and beta-adrenergic antagonist activity,

calcium channel antagonism, and prolongation of the potential and refractory period of the

myocardial tissue which decreases AV conduction and sinus node function (LexiComp).

Amiodarone is now a commonly used antiarrhythmic medications in the United States and can

also be used for atrial fibrillation and atrial flutter. Additionally, it can be used in life-threatening

ventricular tachycardia or fibrillation when previous interventions have failed (Marraffe).

The aspect of the pathway of amiodarone that is most compelling for future refinement

would have to be its wide variety of uses but this medication also has a wide variety of adverse

effects, which could be potential downfall. Different modifications of amiodarone can be useful

in the treatment specifications for various disease and also reduce the adverse drug effects that

accompany this medication.