Early elixir: brompheniramine, a first-generation antihistamine

Industry
By
Dr Leigh Dayton
-

For over 70 years brompheniramine has been used to stifle sneezes … but not for everyone.

Here’s to Daniel Bovet. In the 1930s, the Swiss pharmacologist developed F292, thymo-ethyl-diethylamine. It sounds very ‘so what?’, but in his laboratory at the Pasteur Institute in Paris, Bovet found that the compound countered the severe allergic reaction of histamine in guinea pigs. In other words, he discovered the first antihistamine.1,2 

For his efforts on this and other synthetic compounds, Bovet won the 1957 Nobel Prize for physiology or medicine.1–3

Although F292 was too toxic for people, it kickstarted a rush to create suitable treatments for the sneezes, runny noses and itchy eyes caused by allergies, hay fever and the common cold.1,2

The first human antihistamine, Antergan, was developed in France in 1942. Like Antergan, other first-generation drugs were nearly all derived from F292.1 

Among the new ‘wonder drugs’ was brompheniramine, patented in 1948 and in medical use in 1955. In Australia, brompheniramine is sold over the counter as a component of Dimetapp products.4

How it works

Brompheniramine fights the sneezes and sniffles with two active arms. The first is an antagonist of H1 histamine receptors on the surface of a variety of cells. Among these are airway and vascular smooth muscle cells, endothelial cells, epithelial cells, eosinophils and neutrophils.8–10

Brompheniramine is also a moderately effective anticholinergic agent, thus reducing the binding of acetylcholine to muscarinic acetylcholine receptors.8–10

‘Adverse effects such as drowsiness or sedation, dry mouth, dry throat, blurred vision and increased heart rate appear to be triggered by brompheniramine’s anticholinergic action.’

Use in Australia

Despite advances in antihistamines since brompheniramine hit pharmacy shelves last century, the compound is still marketed for treatment of symptoms of allergic reactions, allergic rhinitis, cold symptoms and hives.5 However its use is not without problems.

Adverse effects

There are reactions to brompheniramine that include drowsiness; dry mouth, nose and throat; nausea; headache; and chest congestion. Vision problems and difficulty urinating are more serious adverse effects.6,11 Older adults may also experience confusion, as well as dry mouth and constipation.7

Adverse effects such as drowsiness or sedation, dry mouth, dry throat, blurred vision and increased heart rate appear to be triggered by brompheniramine’s anticholinergic action.10 

Sleep-wary regulators

The fact that first-generation antihistamines like brompheniramine have a significant sedative effect has pushed experts to question who should use them and how they should be used and sold. 

Of particular concern is evidence that these ‘sedating antihistamines’ have caused aviation and car accidents, and are linked to poorer school performance in children, and behavioural and ‘other adverse effects’ in children younger than 2 years.10 Further research points to ‘accidental or intentional’ overdosing of infants and young children, as well as suicide in teenagers and adults.11

Concern was such that in 2007 an expert panel of the US Food and Drug Administration warned that antihistamines like brompheniramine are ‘potentially dangerous’ to children under the age of 6 years. The FDA recommended they not be used in children younger than 2 years.12

In 2008, the Therapeutic Goods Administration announced that in response to ‘overseas’ reports, it reviewed the regulatory status of ‘non-prescription cough and cold medicines’. Its conclusion: over-the-counter cough and cold medicines should not be used in infants and children younger than 2 years of age.13

Daniel Bovet wouldn’t sneeze at such a warning.

References

  1. Encyclopedia.com. The Development of Antihistamines. 2021.
  2. Shampo MA, Kyle RA. Daniel Bovet―Nobel Laureate in Medicine. Mayo Clinic Proceedings 1999;74(10):1016.
  3. Nobel Prize Outreach. NobelPrize.org. The Nobel Prize in Physiology or Medicine 1957: Daniel Bovet.
  4. Sinha S. Dimetapp. Drugs.com. 2019.
  5. Drugs.Com. Brompheniramine.
  6. U.S. National Library of Medicine. MedlinePlus. Brompheniramine. 2018.
  7. Multum C. Brompheniramine. Drugs.co. 2021.
  8. DrugBank Online. Brompheniramine. 2021.
  9. Toxno. Toxno Substance Profile. Brompheniramine.
  10. Randall KL, Hawkins CA. Antihistamines and allergy. Aust Prescr 2018:41:42–45.
  11. Church MK, Maurer M, Simons FER, et al. Risk of first-generation H1-antihistamines: a GA2LEN position paper. Allergy 2010;65:459–66.
  12. Lavelle P. Thumbs down for cough mixture. ABC Health & Wellbeing. 2007.
  13. Australian Government Department of Health. Therapeutic Goods Administration. TGA announcement. Cough and cold medicines in children. 2008.