1900-current: The evolution of asthma rescue medicine

Photo from an advertisement for Adrenaline Ampoules in the 1909-10

edition of"Therapeutic Notes" by Park Davis and Company

So, epinephrine was discovered, isolated, and then it was synthesized, and this resulted in various epinephrine products. The injected and inhaled versions were found to provide quick relief for asthmatics, and became known as the first asthma rescue medicine. Over time, a synthetic version of epinephrine was made in a lab, and this was refined to come up with safer, stronger rescue medicine. That said, here is the evolution of asthma rescue medicine.

1901:  Adrenaline/ Epinephrine: Takamine patented the technique for isolating the compound. He had connections with Parke, Davis & Company, and so they gained marketing rights. Epinephrine was initially available as a pill. However, physicians soon learned this was not very effective for asthma, and the pills disappeared from the market almost as fast as they arrived. A nasal spray became available, and this was used for both hay fever and asthma. (3, page 156)

Yet what gained the favor of the medical community was epinephrine injections, which seemed to provide instant relief. Epinephrine injections are still available to this day, although, thanks to the advent of modern asthma controller medicines, it is rarely used to treat asthma (although it's available in hospital med carts if needed).

Percy Camps, a general practitioner from Teddington, showed that inhaling epinephrine solution using a nebulizer also benefited asthmatics. And so this became a common method of distributing the medicine to asthmatic airways, thereby eliminating the need to go through the patient's system, thereby minimizing side effects.   (3, page 156)(6, NCBI)

While the reason epinephrine worked was a mystery at first, it was ultimately learned that it mimicked the sympathetic nervous system. The desired effect was relaxation of the muscles that wrap around air passages resulting in airway dilation. It was later discovered to sit on beta 2 receptors lining bronchiolar muscles, causing these muscles to relax, thereby opening airways. When given by injection, this response occurred within 5-15 minutes and lasted 1 to 1.5 hours.

Although, along with the desired effect, the medicine also produced the undesired effects. This was because it also was attracted to beta 1 and alpha 1 receptors lining vessels and the heart. This resulted in increased heart rate and depth, increased blood pressure. The accumulated effect also resulted in increased nervousness and tremors. Still, these side effects were a fair trade offs for ending asthma attacks. Efforts to refine synthetic epinephrine by scientists in order to enhance the desired effect and eliminate the undesired side effects are still ongoing to this day.

Figure 3 -- 1998 picture of epinephrine products

Epinephrine pills are no longer available. Epinephrine injections are available in hospitals, although are rarely used for asthma due to safer medicine. Epinephrine (Epi-pens) and other such products and brands are available for home use, although they are also rarely used for asthma.

During the 1930s, 40, and even into the 1950s, the severest asthmatics may have had access to epinephrine and syringes to inject themselves when all other options failed. In 1985 a nurse taught me how to inject myself when my doctors prescribed epinephrine for home use. My dad injected me twice, and I injected myself once. After the injection I was instructed to use my oxygen tank and inhale 2lpm oxygen for an hour. It worked like a charm every time, and made it so I didn't have to call my doctor or have my parents rush me to the emergency room.

1910: Aerosolized Epinephrine:  This was first introduced as an option for asthma in 1910. A nebulizer solution was introduced in 1929 and marketed under a variety of manes, including Adrenaline, Adrenaline Chloride, and Asthma Nefrin).  The solution was available over the counter to be used with a variety of glass, rubber squeeze bulb nebulizers and atomizers for home use. In the hospital setting the nebulizers could be hooked up to air compressors or, more likely, oxygen tanks.

Aerosolized epinephrine wasn't the ideal asthma remedy because of high doses needed to achieve only minimal breathing relief.  It also wasn't idea, particularly when used at home, because of the effort needed to squeeze the bulb in order to inhale a mist. This would have taken quite a bit of patience by asthmatics.

As better nebulizers were introduced to the market during the 1930s, patient's were able to give themselves epinephrine nebulizer treatments at home. Some would have had access to simpler air compressors to deliver the flow necessary to run the nebulizer, although most asthmatics probably just continued to use the less expensive squeeze bulb nebulizers.

After the inhaler was invented in 1956, the epinephrine was available as the Medihaler (see below) and this was nice because asthmatics could now leave their homes with the comfort of knowing they had their rescue medicine in their pockets or purses. So this would have inspired some decline in nebulizer solution sales.

The Epinephrine solution was taken off the market by the FDA in 1972 due to fears the product was linked to asthma deaths (although this was done with no evidence linking the medicine with asthma related deaths).

1948:  Isoproterenol (isoprenaline):    Isopropyl norepinephrine was synthesized in 1903 as the first modification of epinephrine. It's chemical composition was similar to epinephrine, although it was only specific to beta receptors (both beta 1 and beta 2). (5, page ???)(10, pages 73-74)

The main advantage of Isuprel was that it eliminated the side effect of vasoconstriction that resulted in increased blood pressure. It was introduced to the market in 1948 as Isuprel, thus giving physicians an alternative to epinephrine. Like epinephrine, the bronchodilating effect lasted 1 to 1.5 hours.

It was available as an injection and as a solution to be given with one of the nebulizers available at the time.

Figure 2 -- 1954 ad for Norisodrine Inhaler

1949: Norisodrine: It was a dry powder bronchodilator that was inhaled using the Aerohaler, the first modern dry powder inhaler (DPI). It was released by Abbot laboratories in 1949 as the first marketed dry powdered inhaler (DPI). The active ingredient was isoprenaline sulphate.

Technically speaking, it was the first rescue inhaler. It didn't really get much of a chance to gain the love of asthmatics mainly due to the invention of the metered dose inhaler (MDI) in 1957. Just imagine, if the MDI wasn't invented, asthmatics everywhere would probably have an aerohaler. The market for DPIs might have taken off sooner than it did.

A.R. Clark, in a 1995 article for Aerosol Science and Technology, described this inhaler this way:

"The device consisted of 'sifter' cartridges containing the powdered dose out of the cartridge and a mouthpiece through which the aerosol was inhaled. There was very little control over the delivered dose, other than patient symptoms titration, and there was no dispersion mechanism inside the device to aid aerosol generation." (2, page 382)

Each glass vile contained three smaller vials (sifter cartridges) that were set on the inhaler device.  The patient then inhaled the powder through the nose.  There were some disadvantages to this device, the most significant was the release of the MDI in 1957, which was by far more convenient for asthmatics.

The Aerohaler was also used in the late 1940s and 50s as a means to deliver penicillin.  A modern version of the Aerohaler was remarketed and available in some countries, yet it has little in common with the original.

1951: Isoetharine: This medicine was first synthesized in 1936 and introduced in Germany as Aleudrin in the 1940s.  It later entered the U.S. market as Bronkosol in 1951 as the first beta 2 specific rescue medicine. Fittingly, it was marketed as the first beta 2 specific aerosolized bronchodilator.

Because it was only attracted to beta 1 receptors, it had a stronger bronchodilating effect than than epinephrine. However, a down side is that it still did have some beta 2 effect, although less than Isoproterenol. Still, it was desirable because of the decreased cardiac affect.

Like epinephrine and isoproterenol, the medicine worked fast and lasted 1 to 1.5 hours. Also like epinephrine and isoproterenol, it was a top asthma remedy during the 1940s, 50s, and 60s.

(Check out AARC Virtual Museum for more pictures)

Medihaler Epi with its 3 inch mouthpiece
(Image obtained Google Images)

1956:  Medihaler Epinephrine: The MDI was invented in 1956, and that same year the FDA approved the Medihaler Epi. It was marketed by Riker Laboratories (changed to 3M Pharmaceuticals in 1970) as the first metered dose inhaler. Not surprisingly, it quickly gained the favor of both physicians and their patients. 

Like nebulized epinephrine, inhaler epinephrine produced only moderate relief, although it was still relief regardless. The inhaler also made quick relief portable and convenient to use, and this, more than anything, won the hearts of asthmatics.

It was usually prescribed for 2 puffs 2-5 minutes apart every 4-6 hours as needed. The medicine was also available over the counter, and without a physicians prescription. Many asthmatics, as you might imagine, used it more frequently than this to obtain relief and to relieve asthma related anxiety. A rise in asthma related deaths lead to concerns that the inhalers were the culprit. Some evidence pointed to lack of education as the culprit, resulting in inhaler educational campaigns to assure adequate inhaler technique and compliance.

The Medihaler Epi was an option for asthmatics until 1998 when 3M decided to pull the plug on the product. The reason sited was the inability to guarantee a quality product.  The company stated that the product was once thought to have a shelf life of three years, and this had been reduced to 18 months. So guaranteeing a quality product was no longer possible. (8, page 619)

It should be noted that by this time there was better and safer rescue medicine on the market, and there continued to be concerns about having a rescue inhaler available over the counter, of which this product was for many years. Most asthma experts believed if someone was having trouble breathing that they were probably better served seeking the medical advice of a physician, rather than treating themselves. Those concerns aside, while other rescue medicines required a prescription, the Medihaler was grandfathered in.

Primatene Mist inhale

Other generic epinephrine inhalers remained on the market, such as Primatene Mist. Wyeth and Armstrong (a subsidiary of Amphastar Pharmaceuticals) continued to market their version of an epinephrine inhaler remained on the market until it was phased out and ultimately discontinued on December 31, 2011.  This was partly due to the Montreal Protocol that required a phase out of CFC propellants.

Makers of over the counter inhalers fought the ban, although they lost their appeal.  Primatene Mist was finally discontinued on December. 31, 2011. As of this writing, no over the counter CFC epinephrine inhaler is available. An FDA advisory panel voted not to recommend an over the counter HFA epinephrine inhaler. (9)\
A 2005 National Health Interview Survey by the Centers for Disease Control and Prevention (CDC) determined that 7.7% of the U.S. population owned an epinephrine inhaler, which would amounted to about 23 million people, according to FDA.gov.

This discontinuation did not effect non inhaler epinephrine products. While not yet approved by the FDA, an HFA version was considered. Wyeth also contemplated an epinephrine DPI, although this is not a viable option at this time, according to FDA.com.

Medihaler Iso
(pharmaceutical-journal.com)

1956:  Medihaler Isoproteronol:  In 1956 the Medihaler-Iso was also approved by the FDA and introduced to the U.S. market in 1957.  It was the most popular asthma medication from 1957 to 1970. It may also be referred to as Isuprel Mistometer.

Another brand name to eventually enter the market is the Isuprel Mistometer and the vapo-n-iso solution delivered with the Bronkometer by Breon Laboratories.  The 1978 Physicians Desk Reference recommended that anyone requiring more than three treatments in 24 hours should be under the close supervision of a physician. I do not know when this inhaler stopped being marketed.

It was usually prescribed for 2 puffs 2-5 minutes apart every 4-6 hours as needed.

1960s:  Susphrine: This was epinephrine formulated in such a way that it lasted 6-8 hours. Doctors loved this because they could give patients susphrine along with a systemic steroid.  Then they could send patients 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.  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.

1970s: Aerolone:  Remember the initial theory regarding epinephrine, the one where the vacoconstricting properties of epinephrine were thought to relieve congestion and this made breathing easier.  Aerolone again played on this theory. It was a combination of 0.35% isoproterenol (a beta receptor agonist) and cyclopentamine (an alpha receptor agonist). It was available in a dose of 0.5cc for nebulizer treatments. The belief was that the combined alpha and beta effects would produce both bronchodilation to open airways and vasoconstriction to decrease airway congestion. (1, page 857)

1970s:  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 dry powdered inhaler (DPI) was marketed but never available in the U.S. It had a stronger beta effect than metraproteronol.

By the 1980s it was the main alternative to metraproteronol, with the later being the more popular alternative. The medicine was thought 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.

Figure 4 --Ventolin solution came in a bottle

 with nipple syringe.  The syringe was used

to draw up 0.5cc of the solution, and it was squirted

into the nebulizer cup and mixed with 3cc of

oth normal saline. Concerns about

contamination lead to plastic ampules with

pre-measured doses of albuterol and

normal saline in the early 2000s.

Albuterol solution had a similar design,

only it had a distinct orange nipple. 

1973:  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.  Still, it was the first beta 2 specific rescue medicine that lasted more than 4-5 hours.

It was available as a solution for nebulization and as an MDI.  The solution came in a small, dark brown bottle with a bright orange nipple adapter 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. The inhaler was white. The inhaler was phased out as Albuterol gained acceptance during the 1980s and early 1990s.  In 2010 production of Alupent was discontinued altogether, mainly due to the acceptance of albuterol as a stronger and safer medicine. .


1980:  Albuterol:  This was introduced as the first beta 2 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.

Figure 5 -- Ventolin inhaler.  Like the inhaler
in general, it has not changed much over
the years. 

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 beta 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 as needed. In emergency rooms and hospitals, higher doses, or continuous treatments, are sometimes given to treat stubborn cases of asthma. In fact, most physicians consider continuous albuterol nebulization as effective and safer than epinephrine injections.

It is generally recommended, however, that asthmatics seek medical attention if they need their rescue medicine more frequently than 4-6 hours. In other words, asthmatics should stick to the dose and frequency recommended by their physicians.

The Inhaler Float Test.
This was the only way
to tell how much medicine
was left in the inhaler.
Albuterol HFA inhalers
come with a counter,
so the float test
is no longer recommended.

The solution was initially obtained in a small, brown glass bottle and drawn up with a hypodermic needle or the nipple adaptor attached to the cap.  During the late 1990s and early 2000s it became available in single dose plastic amps premixed with normal saline. This change was made due to infection control. Plus this made it easier for patients, who no loner had to mix the solution with normal saline on their own.

The medicine worked so well, with side effects being so negligible, that it became the most popular asthma medicine during the 1980s and 1990s, and the most profitable asthma medicine of all time.

By 1999, the product was available as 17 unique brand names including ProAir, AccuNeb and Vospire.

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 inability to generate enough flow during asthma attacks.

Ventolin inhalers with counters.
Asthmatics now knew
how many doses remained.

Also 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 ( a breath actuated HFA inhaler available in the U.K). 

According to drugpatentwatch.com, most patents for HFA inhalers are set to expire by 2020.

Another thing to note here is the color code system regarding inhalers. There is no law, but considering most MDI inhalers look alike, a color coding system was established where rescue inhalers were blue and controller inhalers were brown. So, most albuterol inhalers are brown. However, there have been generics available over the years were white or orange, and thereby their manufacturers did not adhere to the color scheme. As of this edit on April 24, 2017, there are three albuterol inhalers:

• ProAir HFA, which is red
• ProAir Respiclick, which is white with red cap and lettering
• Proventil HFL, which is yellow with an orange cap
• Ventolin, which is blue with a dark blue cap

Maxair Autohaler

1992:  Pirbuterol:  The product was introduced in the 1980s,  and was approved by the FDA in 1992 and marketed as Maxair.  It's composition was similar to Albuterol, although it improves breathing in less than 5 minutes as compared with Albuterol's 15 minutes. The side effects were similar to Albuterol. (6)

The neat thing about was it was available as an Autohaler.  This was a
breath actuated device, which coordinated the medicine with the patient's breath, resulting in better drug deposition to airways. It was phased out by 2013.

Sticking with the traditional color coding system, Maxair was a light blue inhaler with a white cap.

1990s: Bitolterol  This product was marketed by Sanofi-Synthelabo in the early 1990s. It was a beta specific medicine that had an onset of 2-5 minutes and lasted 5-8 hours. It was never widely accepted and production stopped in 2003, according to FDA.gov.

1996: Albuterol/ Ipatropium Bromide Inhaler:  A Combivent CFC inhaler was approved by the FDA in 1996, according to FDA.gov. It was commonly prescribed for patients with chronic lung diseases during the 1990s and 2000s. It was never a top line medicine for asthma, although it has always been an option.  The recommended dose is 2 puffs every 4 hours as needed, or simply four times per day. It was discontinued on December 31, 2013.

However, Boehringer Ingelheim announced via press release on October 7, 2011, that the FDA had approved the Combivent Respimat. The inhaler device does not use a propellant, and delivers a slow mist of the medicine for inhalation.

It is my opinion that there are far better options than the albuterol/ ipatropium bromide combination, and these include Spiriva, and the combination of long acting bronchodilators and inhaled corticosteroids. Still, based on previous studies, and the slow speed at which the medical community latches on to new ideas, this combination inhaler will continue to be prescribed for some time.

Now, you also have to add into here the dogmatic nature of many people with chronic lung diseases. Once you find a medicine, or a combination of medicines, that seem to work, you don't want to change. I have found this to be true by my own experience as well as by observation of my COPD patients in the hospital setting. Other than for profit, the main reason I think that Combivent Respimat is even an option today is by public outcry among the COPD community. I have no evidence of this, although it's my own personal theory.

Combivent Respimat requires two inhalations four times every day. The medicine can also be used as a rescue inhaler, although this is generally not recommended.

Combivent was generally a white inhaler with some green and some brown on the label. The cap was brown. The new Respimat Combivent is a gray device with a brown cap and some brown on the label.

1996: Duoneb:  Approved by the FDA in 1996?  It's  solution that combines 0.5cc Albuterol with 2.5 mg Atrovent and 0.3 cc normal saline.  I believe it was the first medicine to come premixed in plastic ampules. Like combivent, it's most commonly prescribed for COPD, although is an option for asthma and other lung disorders as well. From my experience, it is very common among the medical community for patients in the emergency room and hospital setting regardless of diagnosis. Various studies (such as Dorinsksy 1999) showed that the combination of albuterol and ipatropium bromide is superior to individual agents.

1999:  Levalbuterol Solution:  This medicine continues the effort to find a better and safer asthma rescue medicine. The r-isomer in albuterol was shown to cause bronchodilation, while the s-isomer was shown to cause refractory bronchospasm.  At least this was one theory devised to show why so many asthmatics seem to become addicted to their inhalers, and why so many respiratory therapists are diagnosed with asthma.

Levalbuterol is basically albuterol without the s-isomer. It was approved by the FDA as Xopenex in 1999, and was marketed by  Sepracor as being stronger than albuterol (lasting 6-8 hours compared to 4-6 hours for albuterol), resulting in fewer side effects.

Salespeople working for Sepracor initially  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, sort of.

A couple problems ensued. One was that levalbuterol was very expensive compared to albuterol, which costs basically pennies on the dollar. For instance, as of 2012, one amp of levalbuterol cost $4.17 while one amp of albuterol cost only $0.75.

At the same time, clinical evidence, and subsequent studies (Ralston, 2005) did not support the initial claims by Sepracor. This resulted in many hospital administrators creating protocols recommending to physicians that they prescribe albuterol and reserve levalbuterol to rare instances when albuterol is suspected of, or feared to, cause side effects.

In my own personal experience, this has resulted in a significant decline in levalbuterol orders within the hospital setting. I have yet to look into this, although I would imagine levalbuterol sales have declined. I will look into this later.

Regardless, the medicine is 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 similar 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)

Levalbuterol Inhaler. In March of 2005, Sepracor announced via press release that the FDA had approved an HFA levalbuterol inhaler. It has since been introduced to the market as a light blue inhaler. In staying true to the color coding system, Xopenex HFA is a light blue inhaler.

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, https://c.aarc.org/marketplace/reference_articles/07.00.0854.pdf, accessed 4/12/16
2. Clark, A.R., "Medical Aerosol Inhalers: Past, Present, and Future, Aerosol Science and Technology, 1995, 22:4, 374-91, DOI, http://www.tandfonline.com/doi/pdf/10.1080/02786829408959755, accessed 4/12/16  
3. Sneader, Walter, "Drug Discovery: A History," 2005, Wiley, Great Britain,  page 155-157. (Sneader provides a very thorough history of the discovery of hormone therapy in the later portion of the 19th century.)
4. " Jockichi Takamine ," Encyclopedia Britannica.com,  http://www.britannica.com/EBchecked/topic/581144/Jokichi-Takamine, accessed 3/6/13
5.  Jackson, Mark, "Asthma: A Biography," 2009, Great Britain, Oxford University Press
6. Barnes, Peter J, "Drugs for Asthma," British Journal of Pharmacology, January, 2006, http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1760737/, accessed on 4/14/16
7. "50th Anniversary of the first pMDIs," Pharmaceutical Journal, December 23, 2006, volume 277, page 795, http://www.pharmaceutical-journal.com/news-and-analysis/news/50th-anniversary-of-the-first-pmdis/10002907.article, accessed 5/15/16
8. Letters to the Editor, "Withdrawal of the Medihaler-epi/ Adrenaline Medihaler: comments of the Subcommittee on insect venom allergy of the EAACI," Allergy, 1998, 53, pages 619-620, http://onlinelibrary.wiley.com/doi/10.1111/j.1398-9995.1998.tb03939.x/pdf, accessed 4/15/16
9. Bass, Pat, "Are Primatene Mist And Generic Epinephrine Inhalers Safe?, About.com, updated January 18, 2016, http://asthma.about.com/od/treatmentoptions/a/art_primatene_mist.htm, accessed 4/15/16
10. Waring, Nancy, "Harvard Medical School: Guide to taking control to taking control of asthma," 2003, New York, Simon and Schuster,