Wednesday, May 4, 2016

1800-2012: Evolution of back-door bronchodilator

One of the oldest and most popular asthma medicines historically are anticholinergic or muscarinic medicines. The exact mechanisms to how these medicines worked remained a mystery for most of history, so the terms anticholinergic and muscarinic are recent terms. What was known early in our history is that inhaling the medicine offered relief for asthma attacks.

Ancient Egyptian medical documents reported taking dried and crushed herbs, mainly belladonna, and placing them on heated bricks. Then the asthmatic, or the person suffering from asthma-like symptoms, inhaled the medicated smoke and was offered some relief. This was among the most common asthma remedies in Egypt.

At different times in our history, various other civilizations inhaled either belladonna, or other members of this family plants. The common name is the nightshade family, otherwise known as the Solanaceae family of plants. They include:
  • Datura stramonium 
  • Atropa belladonna 
  • Hyoscyamus niger (henbane) 
  • Lobelia inflata.
As the ancient physicians discovered, the best effect was obtained when the medicine was inhaled, and in this way, it was used as a topical applied directly to the lungs. Over time, different methods were used for inhaling the medicine, which included:

1.  Burning herbs: Leaves, roots and stems from the herbs Belladonna and stramonium 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 offered some relief. This method was first recorded in 4000 BC, yet it was probably done long before this.

2.  Pipes:  The sun-dried products of the herbs were ground, and the powder stuffed into crude pipes, lit, and the medicinal smoke inhaled.  This technique was discovered for the modern world in 1803 for Europe and the U.S. and the asthma cigarette craze began.

3.  Cigarettes: The powder was rolled into small paper and smoked cigarettes and cigars.  This technique was commonly used in India and was discovered for the modern world in the early 19th century. An asthma cigarette craze began around 1879 and lasted until the middle of the 20th century.

4.  Pills:  During the 19th century the medicine was formed into pills that were taken by mouth.  A popular brand was Potter's Asthma Pills.  These were common from around 1880 to 1950s.

Ad for Ozone Paper
showing endorsement
by Dr. Thorowgood
(1891)
5.  Nitre/ Ozonepaper:  By the 1850s paper was impregnated with potassium nitrate, strammonium, or belladonna and ignited to produce fumes that were inhaled as a treatment for spasmodic asthma.  By 1973 this was a common mode of treatment and recommended by Dr. John Thorowgood in the British Medical Journal.  (1)  (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.  Nebulizers/ Inhalers:  During the 19th century various nebulizers and inhalers were invented to help asthmatics inhale various solutions of the medicine.   Nebulizers, of course, were fine tuned in the 1930s, and modern inhalers were fine tuned during the 1950s.

As scientists and Pharmaceuticals worked with the plants, they learned, in 1833, that the active ingredient inside it was atropine.  From there they learned how to synthesize the medicine to create modern anticholinergics.

These include:

1.  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 during the 1950s.  The medicine was still prescribed for asthma during the 1980s, although by the 1990s was phased out due to a synthesized anticholinergic medicine with fewer side effects. I was prescribed this medicine in 1985 and took it up to four times per day until around 1990.

It was ultimately learned that the medicine worked by blocking the effects of the parasympathetic nervous system. This system releases a neurotransmitter called acetylcysteine which binds to muscarinic receptors that are randomly scattered along the bronchial smooth muscle. This causes bronchospasm, increased secretions, and asthma symptoms.

Prior to the 1990s, this parasympathetic pathway was thought to be the main cause of bronchospasm in asthma. Atropine and Atrovent worked by binding with muscarinic receptors, thereby preventing acetylcholine from attaching to them, thereby blocking acetylcholine. The medicine became known as anticholinergic or antimuscarinic medicine.

It was at this time, during the 1990s, that researchers learned that most cases of asthma involved some degree of underlying airway inflammation (10),  the severity of which determined how severe a person's asthma was. This inflammation worsened due to exposure to asthma triggers, resulting in bronchospasm, increased mucus production, and asthma symptoms.

It was learned that the best medicines for treating this bronchospasm and underlying airway inflammation were beta 2 adrenergic medicines and inhaled corticosteroids. At this time, anticholinergic medicine was relegated to second-line asthma medicine status, as opposed to front-line status. So, this was another reason most asthmatics are no longer prescribed anticholinergic medicine.

Atrovent Inhaler
2.  Ipratropium Bromide (Atrovent):  This is a synthesized anticholinergic, and it was first introduced in Germany in 1975, followed by the rest of Europe by the late 70s.  It was available both as a solution to be nebulized and as an inhaler, and it was prescribed four times per day.  An HFA inhaler was approved by the FDA in 2004.  I was prescribed this medicine in 1990 and took it up to four times a day until around 1995.  It was initially a top line asthma medicine, although better medicines have replaced it.  I believe the inhaler was phased out in favor of the new Ipatropium Respimat. (3) (4)

As a side note here, up until the mid-1990's, atropine, and later Atrovent, were top-line asthma medicines. Up until this time, the main pathway of bronchospasm was thought to be the parasympathetic nervous system. By this, researchers understood that atropine

3.  Oxitropium Bromide (Oxiven, Tersigen)This was another synthesized anticholinergic released along with ipratropium bromide.  It was marketed as both an inhaler and solution.  Because it was available in higher doses, the frequency was only three times per day.  This medicine was never approved by the FDA for sale in the U.S. (6)

10.  Combivent:  This is a combination of Albuterol and Ipratropium bromide in an inhaler form. It was approved by the FDA in 1996 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 was introduced to the market as a replacement (see Combivent Respimat)
Combivent Inhaler

 11.  Duoneb:  This is a combination of albuterol and ipratropium bromide premixed in plastic amps with 0.3cc of normal saline. It was introduced in the early 1990s and approved by the FDA in 1996.  The medicine was nice because it made for a quicker breathing treatment, as compared to mixing separate amps of albuterol and ipratropium bromide, both with 3cc premixed.  It continues to be a top line treatment for COPD, although is an option for asthmatics.
Spiriva HandiHaler

12.  Tiotropium Bromide (Spiriva Handihaler): This dry powdered inhaler was introduced to the market in Europe in 2002 and the U.S. in 2003. It's the first long-acting back-door bronchodilator, meaning it only needs to be taken once a day.  Studies show it is more effective than ipratropium bromide in improving lung function. It is recommended as a top line treatment for COPD.   (7)

Combivent Respimat
13.  Combivent Respimat: This is the new version of Combivent approved by the FDA in 2012. 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. The medicine was in demand because a non CFC version of Combivent was needed.  (8)

Studies show this type of medicine may produce mild bronchodilation and mild breathing relief. Personally, I never noticed any difference with the medicine. However, modern evidence suggests the medicine, when used daily, may act as a preventative medicine, keeping lungs dilated long term.

Modern studies have found that anticholinergics that anticholinergics don't benefit asthmatics as once was suspected, and so, while they remain an option, they are no longer a top-line option.  Spiriva continues to be a top line option for COPD, as studies show it improves lung function. Atrovent and Combivent are slowly being phased out in favor of the newer medicines.

Duoneb continues to be an option for COPD patients, although even it has seen better days.  Some physicians are phasing this medicine out in favor of long acting medicines that only need to be taken once or twice a day, such as Spiriva, Brovana, and Pulmicort.

So what started out as a medicine that was sporadically recommended and inhaled as smoke around a primitive cooking fire, has evolved into a medicine that is taken in the form of simple inhalations that are conveniently and safely delivered as simple inhalations.





Anticholinergics (or muscarinics) are medicines that, once inhaled, sit on cholinergic (or muscarinic) receptor sites that sit along bronchial smooth muscles. It binds to and sits in these receptor sites, thereby preventing the neurotransmitter acetylcystine from binding to them.

of the neurotransmitter acetylcysteine to prevent it from causing bronchospasm. Because the medicine is blocking a natural response as opposed to actively causing bronchodilation, it is often referred to as a "back-door bronchodilator."



    The first "back-door bronchodilators" used came from the nightshade family of plants called Solanaceae, and were often included in ancient recipes for asthma remedies.  Some common plants used were:
    
    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
    10. Wright, Rosalind J., Mario Rodriguez, Sheldon Cohen, “Review of psychosocial stress and asthma: an integrated biopsychosocial approach,” Thorax, 1998, December, http://thorax.bmj.com/content/53/12, accessed 7/18/17
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