Bretylium

Discovery and Commercialization of Bretylium/Bretylium Tosylate (Bretylol)

Discovery

History of Development

In the 1950s researchers at Leeds University began studying phenylcholine ethers in an attempt to find a drug that could affect adrenergic nerve function. Out of the drugs studied, Bretylium was chosen for clinical trials since it exhibited the least cholinomimetic properties⁽⁴⁾.

Source of Compound

Bretylium (which is often stabilized by tosylate) is not a natural product. It is synthesized by the quaternization of o-bromo-N, N-dimethylbenzylamine with ethyl-p-toluenesulfonate⁽⁵⁾.

Mechanism

The exact mechanism of Bretylium is not completely understood, but its general path is known. After administration into the blood or muscle, Bretylium is selectively taken up into peripheral adrenergic nerve terminals, where it causes an initial release of norepinephrine that creates a sympathomimetic effect. After this initial release, Bretylium inhibits the release of norepinephrine, creating an adrenergic blockade to selectively inhibit sympathetic impulses. Ultimately, Bretylium blocks the uptake of epinephrine and norepinephrine at adrenergic nerve endings^(1)(2)(5).

Effect/Treatment

In addition to blocking the uptake of norepinephrine, Bretylium has the direct myocardial effect of prolonging action potentials and effective refractory periods by inhibiting the conductance of potassium (due to the elevation of the ventricular fibrillation threshold). Bretylium takes around an hour to reach its peak effectiveness, and effects can last from 6 to 24 hours^(1)(2)(5).

Because of these properties Bretylium is an effective anti-arrhythmic agent that can be used in treatment for Ventricular Fibrillation (VF), Ventricular Tachycardia (VT), and any other ventricular arrhythmias.

Adverse Reactions

During initial development problems found with Bretylium included dizziness, increased frequency of micturition, muscle weakness and parotid pain. Although the biggest issue in development was the increase in patient tolerance, which could not be countered by increasing drug dosage⁽⁴⁾. However, more problems were discovered after the initial development stage. Some of the most prominent adverse effects of Bretylium are caused by the initial release of norepinephrine. This initial release can illicit sympathetic responses in the patient, which is the opposite of what is desired. Some effects from these responses can include transient hypertension and an increase in the frequency of arrhythmias. The primary adverse effect caused by the desired mechanism of blocking norepinephrine is hypotension (postural and supine). It has also been found that when rapid intravenous administration is used with Bretylium that it can cause nausea and vomiting^(1)(2)(5).

Improvement

At first Bretylium was chosen as a promising drug for its ability to affect adrenergic nerve function with minimal cholinomimetic properties, and tolerable adverse effects⁽⁴⁾. However, as time went on it became clear that these effects were not tolerable, and it was not worth modifying the drug when other alternatives had been found. Additionally, the materials for synthesis are scarce⁽⁴⁾. The main alternative for Bretylium is Amiodarone, which is the natural active ingredient in the Khella plant. Amiodarone shares some adverse effects with Bretylium such as dizziness and hypotension, but does not have a tolerance issue, and is easy to create⁽³⁾. Which is why it is currently the most popular anti-arrhythmic agent, and why Bretylium is no longer used in the clinic.

Commercialization

Commercial Aspects

Although Bretylium began to be used for treatment in the 1950’s, it was not submitted for FDA approval until 1976 by Ganes Chemical Incorporation. After the Ganes company approval, new drug applications began to be submitted to the FDA. Between 1982 and 1989 16 NDAs for 4 different types of Bretylium Tosylate were approved by the FDA. Out of these applications, Hospira (Which was later bought by Pfizer) was the first and largest company to get approval. Hospira began to market and sell Bretylium Tosylate under the brand name Bretylol, and over time other companies withdrew their NDAs until Hospira was the only remaining company with an NDA⁽⁹⁾.

Intellectual Property

The first patent for the use of Bretylium Tosylate as an antiarrhythmic agent was granted to Marvin Bacaner at the University of Minnesota in 1969⁽⁷⁾. Since then there have been hundreds of patent applications for things relating to Bretylium Tosylate, but only a handful have been granted. The only trademark that has been granted in relation to Bretylium Tosylate is Hospira’s brand name Bretylol.

Regulatory Information

Bretylium Tosylate has not shown any issues with toxicity, or other safety concerns. However, it has a very large sourcing problem due to the raw material issues ⁽⁸⁾. Because of this Hospira withdrew its NDA in 2011, making Bretylium Tosylate permanently unavailable in the United States. Since its withdrawal had nothing to do with safety or effectiveness concerns Bretylium Tosylate remains on the FDA’s discontinued drug list⁽⁶⁾.    

Sources

1. Anderson JL. Antifibrillatory versus antiectopic therapy. Am J Cardiol 1984; 54: 7A-13A.

2. Cummins, R. O. (1994). Textbook of advanced cardiac life support. Dallas, TX: American Heart Association.

3. Cunha, J. P. (2017, April 18). Amiodarone (Nexterone): Side Effects, Dosages, Treatment, Interactions, Warnings. Retrieved September 23, 2018, from https://www.rxlist.com/consumer_amiodarone_nexterone/drugs-condition.htm

4. Green, A. (1982). The discovery of bretylium and bethanidine. British Journal of Clinical Pharmacology,13(1), 25-34. doi:10.1111/j.1365-2125.1982.tb01333.x

5. Koch-Weser J. Bretylium. N Engl J Med 1989; 300(9): 473-7.

6. Determination that Bretylium Tosylate Injection, 50 Milligrams/Milliliter, Was Not Withdrawn From Sale for Reasons of Safety or Effectiveness. Food and Drug Administration. December 19, 2011. pp. 78669–70. Retrieved November 5, 2018– via federalregister.gov. 76 FR 78669

7. US 3441649, Marvin B Bacaner, Suppression of cardiac ventricular fibrillation and cardiac arrhythmias with bretylium tosylate, assigned to University of Minnesota

8. Khan, M. Gabriel (December 14, 2005). Encyclopedia of Heart Diseases. Academic Press. p. 221. ISBN 978-0-12-406061-6. Retrieved 2015-07-01.

9. PubChem. (n.d.). Bretylium tosylate. Retrieved November 5, 2018, from https://pubchem.ncbi.nlm.nih.gov/compound/Bretylium_tosylate#section=Discontinued-Drug-Products&fullscreen=true