Amiodarone

The Discovery of Amiodarone

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).

Amiodarone is currently manufactured by Mayne Pharma in Australia and Pfizer under the brand name Cordarone (Pfizer and Mayne Pharma). It is also orally available under the names Pacerone produced by Upsher-Smith Laboratories, Inc (wikepedia). It is also available in Australia and New Zealand under the name Cardinorm and Rithmik along with other generic names. In South Africa, this medication is produced by Atlansil and is called Roemmers (Wikipedia). Amiodarone produces about 5% Mayne Pharma’s revenue This medication is distributed through a number of distributors including Parchem and AuroMedics (Amiodarone HCl injections).

The patent of intravenous amiodarone was signed on July 1^st, 2003 with an initial date of November 12^th, 2002 and a patent number of 6,479,541 B1. The inventors for amiodarone are James E. Kipp, Mark J. Doty, Christine L. Rebbeck, and Jan Y. Eilert. The patent relates to amiodarone as an antiarrhythmic agent used as a parenteral solution for intravenous infusion. It states that amiodarone is a surfactant-free parenteral solution that is suitable for intravenous administration without needing to dilute. It also states that the solution is from 0.2-10mg/mL and a buffer solution of lactate buffer, methanesulfonate buffer, or a combination of the two buffers (Kipp).

The European Myocardial Infarct Amiodarone Trial (EMIAT) and the Canadian Amiodarone Myocardial Infarction Trial (CAMIAT) were two trials that looked at the post-myocardial infarction primary prevention using amiodarone. Both of these studies showed that amiodarone reduced arrhythmic but not overall mortality. In the Grupo de Estudio de la Sobrevida en la Insuficiencia Cardiac en Argentina (GESICA) and Amiodarone in Patients with Congestive Heart Failure and Asymptomatic Ventricular Arrhytmia (CHF-STAT) studies, amiodarone was also used for patients with congestive heart failure as a primary prevention strategy. In the CHF-STAT, amiodarone was showed to have a trend toward improved survival in nonischemic cardiomyopathy patients (Naccarelli).

The United States Food and Drug Administration made a warning about the life-threatening slowing of the heart rate that could occur when amiodarone was taken with Harvoni (ledipavir/sofosbuvir) or Sovaldi (sofosbuvir), both used to treat hepatitis C infections. This warning occurred in March 2015 and health care professionals were recommended to no prescribe either of this medications with amiodarone. Most of the reported patient cases were able to recover after the discontinuation of the one of the medications, but one patient died due to cardiac arrest and three patients required placement of a pacemaker to regulate their heart rhythms. The cause for these events was not determined but these drugs are still being monitored for these heart-related events (Center for Drug Evaluation and Research).

            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.

References

(2007) Ammi visnaga (Linn.) Lam. In: Indian Medicinal Plants. Springer, New York, NY

Marraffe, J. (2014). Amiodarone. [online] Encyclopedia of Toxicolgy. Available at: https://www-sciencedirect-com.ezproxy.uky.edu/science/article/pii/B9780123864543006916 [Accessed 21 Sep. 2018].

Online.lexi.com. (2018). Login. [online] Available at: https://online.lexi.com/lco/action/doc/retrieve/docid/patch_f/6332# [Accessed 21 Sep. 2018].

Green, A F. “The Discovery of Bretylium and Bethanidine.” British Journal of Clinical Pharmacology 13.1 (1982): 25–34. Print.

“Amiodarone.” Wikipedia, Wikimedia Foundation, 30 Oct. 2018, en.wikipedia.org/wiki/Amiodarone#History.

Kipp, James E, et al. Amiodarone-Containing Parenteral Administration. 12 Nov. 2002.

Naccarelli, G V, et al. “Amiodarone: Clinical Trials.” Current Opinion in Cardiology., U.S. National Library of Medicine, Jan. 2000, www.ncbi.nlm.nih.gov/pubmed/10666663.

“Mayne Pharma Reports.” Maynepharma.com, 9 Sept. 2014, www.maynepharma.com/media/1348/rodman-and-renshaw-presentationseptember-2014.pdf.

AuroMedics Pharma LLC. “Amiodarone HCl Injection.” AuroMedics Pharma LLC, 8 July 2018, auromedics.com/products/amiodarone-hcl-injection/.

Center for Drug Evaluation and Research. “Drug Safety and Availability - FDA Drug Safety Communication: FDA Warns of Serious Slowing of the Heart Rate When Antiarrhythmic Drug Amiodarone Is Used with Hepatitis C Treatments Containing Sofosbuvir (Harvoni) or Sovaldi in Combination with Another Direct Acting Antiviral Drug.” U S Food and Drug Administration Home Page, Center for Drug Evaluation and Research, 24 Mar. 2015, www.fda.gov/Drugs/DrugSafety/ucm439484.htm.