1900-current: The evolution of asthma rescue medicine

1944 ad showing glass epi vial 

Editors note:  Click the links provided for further reading and/ or definitions. For a quick peek at my dictionary click here.  

The Evolution of asthma rescue medicine started in the year 1900 with the discovery of epinephrine.  It was the first medicine to rapidly end an asthma attack, hence the term "rescue medicine."

Since that day better and safer rescue medicine have evolved.  Here they are:

1.  Epinephrine (epi): It's the grandfather of rescue medicine. It was discovered in 1900 and first used on an asthmatic in 1903. The medicine worked so great because it was very B2 specific.  The problem was it was also B1 and A1 specific, and therefore caused undesirable side effects.  Regardless, an injection ended an asthma attack within 5-15 minutes and lasted 1-1.5 hours.  At the time it was the best asthma medicine ever, and a godsend to asthmatics.  In 1956 the FDA Medihaler-epi was approved by the FDA, and in 1957 epi became available as an MDI.  The injection is still available for use in emergency situations, although rarely used for asthma.  For more on the inhaler see below.

2. Isoproterenol (iso):  It was synthesized in 1903 as the first modification of epinephrine, and was marketed in the U.S. as Isuprel.  It was also referred to as isopropyl adrenaline and marketed as Isoprenaline overseas. It's chemical composition was similar to epi, although it was only specific to beta receptors, both B1 and B2.  So it still had side cardiac side effects.  The effects lasted 1-1.5 hours.  It was only available as an injection until the 1930s when the electric nebulizer was invented.  In 1956 the Medihaler iso was approved by the FDA, and in 1957 iso became available as an MID.  It was a top line treatment for asthma in the 1940s, 50s and 60s.  It's no longer used for asthma, however is still marketed for other purposes.

3.  Aerolone:  Cyclopentamine was an alpha receptor agonist and it was given with isoproteronol in a solution called Aerolone to limit the cardiac affects.  The beta effect of isoproteronol would dilate the airway and the vasodilating effect of cyclopentamine would decongest the lungs. (1)  I believe this was mainly used in Europe and Australia.  It has since been removed from the market.

4.  Isoetharine:  It was first synthesized in 1936  introduced in Germany as Aleudrin in the 1940s  It later entered the U.S. market as Bronkosol in 1951 as the first B-2 specific rescue medicine, and it was marketed as the first B2 specific aerosolized bronchodilator.  It had a stronger beta effect and less of an alpha effect than epinephrine.  Bronkosol had less of a beta 2 effect than Isopretoronol, yet it was more desirable because of the decreased cardiac affect.  The medicine still only lasted one and a half to two hours.  Like epinephrine and isoproerenol it was a top like bronchodilator for asthma during the 1940s, 50s and 60s.

1998 picture of epi products

5. Susphrine: This was epinephrine formulated in such a way that it lasted 6-8 hours. Doctors loved this because they could give you the shot of susphrine along with a systemic steroid.  Then they could send you home knowing that by the time the susphrine wore off the steroid would kick in.  It became an option for doctors in the 1960s and was commonly used throughout the 70s and 80s before it was phased out and ultimately taken off the market.   Epinephrine and susphrine were used differently by different physicians.  Some just gave you one or the other, and some recommended using epinephrine initially and then later giving susphrine for the longer action.  I wrote more about susphrine here and here.  It was phased out as an option by the early 1990s and is no longer marketed.

6.  Metaproteronol:  It was introduced to the market in 1961, approved by the FDA in 1973, and marketed as Alupent in the U.S. and Metaprel and Oriprenaline overseas. The chemical composition was similar to isoproterenol and therefore it still had some strong cardiac effects. (2)  Still, it was the first B-2 specific rescue medicine that lasted more than 4-5 hours.  It was available as a solution for nebulization and MDI.  The solution came in a small, dark brown bottle with a bright orange nipple adaptor to draw up the recommended 0.3cc of solution to mix with 0.3cc normal saline.  It  was the bronchodilator of choice during the late 1970s and 1980s only to be phased out as Albuterol gained acceptance in the early 1990s.  In 2010 production of Alupent was discontinued.

7.  Terbulatine:  It was introduced during the 1970s as both an MDI and solution for nebulization and injection.  In 1981 three brand names were approved by the FDA:  Bricanyl, Brethaire, and Brethine.  It lasted 4-6 hours, longer than epinephrine, isoetharine and metraproteronol.  A DPI was never available in the U.S. It had a stronger B2 effect than metraproteronol.  By the 1980s it was the main alternative to metraproteronol, with the later being the more popular alternative.  The medicine is believed to be as powerful as Albuterol, yet why it never caught on as a top line asthma remedy in the U.S. remains a mystery. Many physicians chose to use it only when a tolerance to other rescue medicines was suspected.  The medicine is still used in Europe and rarely in the U.S.  The solution is still available, yet terbutaline inhalers were taken off the U.S. market in 2001.



Ventolin solution with nipple syringe

 8.  Albuterol:  This was introduced as the first B2 selective agonist in 1968.  (3) Two products, Allen & Hansbury's Ventolin and Schering-Ploughs Proventil were approved by the the FDA in 1981.  The nebulizer solution was not available until 1987, according to FDA.gov.  Outside the U.S. the product is often referred to as salbutamol and sold under various brand names.  It's also called racemic albuterol.  It's chemical composition is similar to terbutaline with some adjustments.  It's a fast acting bronchodilator and is very specific to B2 receptors, which greatly limits side effects.  It's full effect is usually felt in 15 minutes.  The usual aerosolized dose is 2.5 mg or  0.5cc in 3 cc of normal saline.  It lasts 4-6 hours and is generally prescribed for use every 4-6 hours. While this solution was initially obtained in a small, brown glass bottle and injected into the nebulizer with a syringe or nipple adaptor, it's now available in single dose plastic amps.    This change was made due to infection control. The medicine was ultimately deemed to be so safe that it became the most popular asthma medicine during the 1980s and 1990s, and the most profitable asthma medicine ever.  For home use the medicine was (and still is) prescribed to be used as needed by inhaler or nebulizer route every 4-6 hours.  However, in emergency rooms the medicine was proven to be safe given as often as needed to make breathing easier.  By 1999 the product was available as 17 unique brand names including ProAirr, AccuNeb and Vospire.  (4*)  Most asthma experts now consider Ventolin not only safer but just as effective as epinephrine for severe asthma episodes, and it's for this reason most of its predicessors have been discontinued.  Albuterol continues to be a safe and inexpensive (about $0.75 an amp) bronchodilator.

The first generic albuterol MDI was approved by the FDA in 1995, according to the FDA.gov.  A dry powdered inhaler version of albuterol called the Ventolin Rotohaler was available during the late 1990s, yet it never caught on due to the high cost of production and the asthmatics inibility to generate enough flow.  In 1995 Salbumin was the first HFA albuterol inhaler. Proventil HFA was approved by the FDA in 1996.  The product was made by 3M Health Care and the marketers were Schering-Plough. (*)  This was significant because the product had already been approved by 23 other countries (****) A Ventolin HFA was approved in 2001.  All CFC albuterol inhalers have since been phased out.  Other HFA brands marketed overseas are the Ventolin Evohaler and Ventolin Autohaler, which is a breath actuated HFA inhaler available in the U.K. 


Maxair Autohaler

 9.  Pirbuterol:  The product was introduced in the 1980s,  and was approved by the FDA in 1992 and marketed as Maxair.  It's composition is similar to Albuterol, although it improves breathing in less than 5 minutes as compared with Albuterol's 15 minutes.  The side effects are similar to Albuterol. (6)  The neat thing about Pirbuterol is it's available as an Autohaler.  With this device the medicine is inhaled by force of the patient's breath instead of just being squirted out.  This acts as a spacer and assures improved compliance with the device, and improves medicine deposition in the lungs for a greater effect. Pirbuterol is currently set to be phased out by 2013.

10.  Bitolterol  The early 1990s saw the marketing of Bitolterol as Tornalate,  and it worked similar to epinephrine, isoproterenol, and esoetharine.  It lasts 5-8 hours, was B2 specific, and also had a quick onset of 2-5 minutes.  It was never widely accepted, and in 2003 Sanofi-Synthelabo stopped production, according to FDA.gov.   

11.  Levalbuterol:  This  medicine was introduced to the market as Xopenex in 1999.  While Albuterol has an S-isomer and R-isomer in it's formula, levalbuterol only had the R-Isomer. Other than epinephrine, levalbuterol is the only single isomer bronchodilator on the market. This was initially believed to make the medicine stronger than albuterol and with fewer side effects, although later studies showed the medicine was no better than albuterol.  The debate is ongoing.  The medicine was available in three doses:  0.35 mg, 0.63 mg, and 1.25 mg, all premixed in plastic amps with 3 cc of normal saline.  Studies showed the 0.63 dose was simiilar in effect to the 2.5 mg dose of albuterol.  The 1.25 mg dose was believed to last from 6-8 hours, meaning less medicine would be needed during the course of the day. (10)

Salespeople working for Sepracor had trouble convincing physicians it was any better than albuterol, so they attempted a unique strategy of trying to convince patients, nurses, and respiratory therapist, who would in turn convince doctors.  The marketing plan worked, and now levalbuterol is preferred by many physicians. However, levalbuterol continues to be under patent, which means it costs about $4.17 per amp while albuterol only costs only $0.75 an amp.  For this reason, most hospital administrators recommend doctors stick with the old faithful and less expensive albuterol for most patients.

Primatene Mist inhaler

12. Primitine Mist::  Wyeth and Armstrong (a subsidiary of Amphastar Pharmaceuticals) continues to makret an epinephrine inhaler as Primitine Mist. While similar medicine is only available as a prescription, the epi inhaler was grandfathered in as an over the counter medicine, according to FDA.gov. A 2005 National Health Interview Survey by the Centers for Disease Control and prevcention (CDC) determined that 7.7% of the U.S. population owned one of these inhalers, which would amount to about 23 million people, according to FDA.gov. Asthma experts have been trying to get the medicine off the shelves for years, and finally succeeded when the Montreal Protocol was signed mandating all CFC inhalers be taken off the market.  Primitine Mist was finally discontinued as of December 31, 2011.  This discontinuation did not effect non inhaler epiniephrine products.
While not yet approved by the FDA, an HFA version may soon be available.  Wyeth has since concluded that an epinephrine DPI is available but it's not a viable option at this time, according to FDA.com.

13.  Combivent:  This was an inhaler that combined both Albuterol and the anticholinergic ipatropium bromide .  It was approved by the FDA in 1996, according to FDA.gov.  It is commonly prescribed for COPD patients during the 1990s and 2000s to prevent and treat symptoms.  It was generally not recommended as a top line asthma medicine, although it is another option.  The recommended frequency is 2 puffs every 4 hours as needed, or simply four times per day.  It's set to be discontinued as of December 31, 2013  Recently the FDA approved a new propellant free Combivent Respimat, and this will be available in the  middle of 2012.

14.  Duoneb:  Approved by the FDA in 1996?, it's a solution that combines Albuterol, Atrovent and 0.3 cc normal saline.  It comes premixed in a plastic ampule.  It's yet another option for asthmatics and other lungers when albuterol alone isn't enough to control asthma. This is a very popular medicine to give in hospitals for just about any respiratory ailment (and whether it does any good or not).

Click here for more asthma history.

References: (I'm presently working on modifing these references)

1. Rau, Joseph L., "Inhaled Adrenergic Bronchodilators: Historical Development and Clinical Application," at AARC.org (American Association of Respiratory Care, July, 2000, Vol. 45, number 7),
2. Rau, ibid
3. Rau, ibid
4. *Ahrens, Richard C., et all, "Therapeutic Equivalence of Spiros Dry Powder Inhaler and Ventolin Metered Dose Inhaler," Am. J. Respir. Crit. Care Med., Oct 1, 1999, vol. 160, No, 4, pages 1238-1243
5. "Allen & Hanbury's: Information," About.com, http://www.answers.com/topic/allen-hanburys
6. Rau op cit
7. Rau op cit
8. Murphy, Anna, "Asthma in Focus," 2007, page 122 *
9. *Ahrens, Ibid
10. Rau, op cit

****Barnet, Alt, "First Metered Dose non-CFC Inhaler approved by FDA," The Lancet, August 1996, vol. 348, Issue 9027, page 606

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