1800-2012: Evolution of back-door bronchodilator

Our quest to learn the history of back door bronchodilators took us all the way back to 4000 B.C. when recipes for remedies for asthma-like symptoms were recorded.  In this post I'd like to list some of the back door bronchodilators used over the years.

As a quick refresher, back-door bronchodilators are scientifically referred to as anticholinergic medicine.  These are medicines that, once inhaled, sit on the receptor sits of the neurotransmitter acetylcsteine to prevent it from causing bronchospasm. 

In this way, anticholinergics cause bronchodilation by preventing bronchoconstriction.  This is where the term back door bronchodilator comes from.  When inhaled they cause mild breathing relief, and in this way can help an asthmatic breathe better.  They aren't nearly as effective as rescue medicine, yet prior 1900 were among the few effective options for asthmatics. 

Studies ultimately proved back door bronchodilators dried up secretions to reduce sputum production and improved lung funtion.  Surely the medicine comes with side effects, and this was the main reason pharmaceuticals ultimately tinkered with the herbs and evolved this line of medicine available to asthmatics.

Back-door bronchodilators originally came from the nightshade family of plants called solanaceae, and were included in many ancient recipes for asthma remedies.  Some members of this family include:

1. Datura strammonium
2. Atropa belladonna
3. Hyoscyamus niger (henbane)
4. Lobelia inflata.   

That in mind, the following are the back door bronchodilators:

1.  Burning herbs: Leaves, roots and stems from the herb belladonna were sun dried and crushed by ancient Egyptians, placed on rocks heated on coals, and the asthmatic would roll up stalks of a reed, place one end up to the crushed herbs and inhale the smoke.  Surely this sometimes made asthma worse, yet more often than not the herb provided breathing relief.  This method was first recorded in 4000 BC, yet it was probably done long before this.  Ancient Greek and Roman asthmatics may have used a similar technique.

2.  Pipes:  Herbs like stramonium were likewise ground up by ancient civilizations like Egypt, dried under the hot sun and inhaled in a similar fashion as noted above.  In India the process of inhaling these herbs evolved to stuffing the powder into pipes and smoking them that way.  This technique was discovered in 1803 for Europe and the U.S. and the asthma cigarette craze began. 

3.  Asthma cigarettes: They were used during most of the 19th ccentury, and became a craze among asthmatics in America and Europe around 1879.  Surely there were some risks, but they made breathing easier and had hallucinogenic effects to help ease the feeling of air hunger.  The cigarettes contained belladonna, stramonium, lobelia, henbane and atrovent (see below).  The craze lasted until the 1950s when the inhaler was invented, and asthma cigarettes were taken off the shelves in the early 1980s due to concerns kids were abusing them.  I wrote about these in more detail here.  

4.  Asthma pills:  Belladona, stramonium, and other back-door bronchodilators were available in pill form.  A popular brand was Potter's Asthma Pills.  These were common from around 1880 to 1950s.

Ad for Ozone Paper (1891)*

5.  Nitre paper:  This is something I have trouble picturing, yet drugs.com describes it as "paper impregnated with potassium nitrate that is ignited to produce fumes inhaled as treatment for asthma. (1)
Strammonium and belladonna were available as nitre paper by the 1850s and in 1873 was recommended for the treatment of asthma by Dr. John Thorowgood in the British Medical Journal.  It was burned to relieve spasmotic asthma, and was proven by studies to cause bronchodilation.(2)  It may also be referred to as ozone paper.  One advertisement for the product even mentions Dr. Thorowgood's endorsement (see picture to right.

6.  Various nebulizers and inhalers:  I'm referring to antique versions here, and non electric.  Potter's sold a funnel that acted as an inhaler to inhale strammonium or belladonna.  You can see a variety of these old inhalers by clicking over to the inhalatorium here. While not all these devices may have been used to inhale back-door bronchodilators, it's still neat to check out these old advertisements. 


7.  Atropine:  It was derived from the belladonna plant in 1833, and by 1867 it was isolated and determined to be a component alkaloid of the various nightshade plants found in India, Egypt, South America and other rocky, warm climates.  It was first available for asthma cigarettes, but around the turn of the 20th century was available as a solution to be nebulized.  It ultimately became a top line treatment for asthma.  Ipatropium was introduced by the late 1970s and atropine was ultimately phased out mainly because ipatropium bromide has fewer side effects.   I was prescribed Atrovent nebulizers back in 1985 and this was prepared in a large, dark brown bottle by the pharmacy and 0.5cc was drawn up with a syringe and mixed with 0.3cc normal saline (water) in the nebulizer cut.  The medicine was usually mixed with Alupent. 

Atrovent Inhaler

8.  Ipatropium Bromide: It was among the first synthetic anticholinergic to hit the market (that means it could be made in the lab).  It was introduced to the German market in 1975 and the rest of Europe and U.S. by the late 1970s.  (3)  It was available as a solution to be nebulized and as an inhaler and the recommended frequency was four times daily.  (4)  An atrovent HFA inhaler was approved by the FDA in 2004. (5)  This medicine works equally as well as atropine with fewer side effects. Because it's available in generic forms it continues to be the cheapest back-door bronchodilator on the market.  I was introduced to this inhaler in the late 1980s and phased off it during the 1990s when back-door bronchodilators were no longer considered top line asthma remedies. 

9.  Oxitropium Bromide:  It was released along with ipatropium bromide as one of the first synthetic anticholinergics, and was marketed as Oxivent and Tersigan.  It's an inhaler and solution similar to ipatropium bromide but is available in higher doses, and therefore the frequency was only three times daily. (6)  This medicine has never been approved by the FDA for use in the U.S.

Combivent Inhaler

10.  Combivent:  This is a combination of Albuterol and Ipatropium bromide in an inhaler form.  It was approved by the FDA in 1996 s for the convenience of COPD patients and some asthmatics who don't respond to other top line asthma medications. The medicine was set to be phased out by December 31, 2013, but due to a public outcry a new version of the medicine will be available soon. 

 11.  Duoneb:  This is a combination of Albuterol and Ipatropium bromide premixed in plastic amps with 0.3cc of normal saline. It was also approved by the FDA in 1996.   It was introduced to the market in the early 1990s for a quicker treatment.  It's mostly used in hospitals and by COPD patients, although some studies in the mid 2000s did show that using it in the emergency room can help pull an asthmatic from a severe attack. Other than that, it is not a top line asthma medicine, just another option.  

Spiriva HandiHaler


12.  Tiatropium Bromide:  It was introduced to the market as the Spiriva HandiHaler in Europe in 2002 and the U.S. in 2003.  (7)  It's the first long-acting back-door bronchodilator that only needs to be taken twice a day.  It was proven to improve lung function and has fewer side effects than ipatropium bromide, which in itself is a relatively safe medicine.  The product isn't recommended as a top-line asthma medicine, but is an option for asthma unresponsive to other top-line medicines.  The medicine is recommended for some cases of asthma, but mainly for COPD.  As the medicine has caught on fewer patients have been prescribed ipatropium bromide. 

Combivent Respimat

13.  Combivent Respimat:  This is the new version of combivent approved by the FDA in 2012.  (8)  The device has no propellant, is breath actuated, and delivers a dose that is supposed to provide greater lung distribution of the medicine than a metered dose inhaler. 


References:

1. "Nitre paper," Drugs.com, http://www.drugs.com/dict/niter-paper.html
2. Thorowgood, John, "On Bronchial Asthma," British Medical Journal, 1873, Nov. 22, page 600
3. Sittig, Marshal, "Pharmaceutical Manufacturing Encyclopedia," 1988, vol. 1, New Jersey, page 837
4. Barnes, Peter J., Jeffrey M. Drazen, Stephen I. Rennard, "Asthma and COPD: Basic Mechanisms and Clinical Management," 2008, page 616-17
5. Ipatropium Bromide, package insert, http://bidocs.boehringer-ingelheim.com/BIWebAccess/ViewServlet.serdocBase=renetnt&folderPath=/Prescribing+Information/PIs/Atrovent+HFA/10003001_US_1.pdfingelheim.com/BIWebAccess/ViewServlet.ser?docBase=renetnt&folderPath=/Prescribing+Information/PIs/Atrovent+HFA/10003001_US_1.pdf
6. Barnes, op cit
7. Barnes, op cit
8. "FDA Approves Combivent Respimat (ipatropium bromide and albuterol sulfate) Inhalation Spray," FDA.gov, http://www.fda.gov/Drugs/DrugSafety/InformationbyDrugClass/ucm274684.htm
9. *Picture with much appreciated permission from Inhalatorium.com