Wednesday, January 04, 2012

1933-1957: Research leads to asthma rescue medicine

So hormonal therapy was first used therapeutically in the late 19th century, and by 1901 epinephrine was isolated.  This set off a series of experiments to synthesize and learn about the actions of epinephrine on the body.

It was soon learned that the hormone adrenaline was a neurotransmitter.  It was released by the adrenal gland in response to stress, and attached to receptors that lined smooth muscles and vessels throughout the body.  This results in vasoconstriction that resulted in increased rate and force of the heart, increased cardiac output and blood pressure.  It also caused smooth muscle dilation, including dilation of bronchioles to make breathing easier.

This theory was basically rejected by the medical and scientific community and considered a speculative theory.  Yet in the year 1933 the theory was proven and validated, and slowly but surely these theories were accepted, and interest peaked so much that the two of the researchers responsible for this theory were given the noble prize.

This knowledge was extremely important for asthmatics, because the more scientists, pharmacists and physicians knew about how these medicines worked, the better medicine they could create. Once the theory was accepted, scientific progress continued.

1936: Iseotharene was synthesized as the first successful modification of epinephrine. (1)

1940s: Iseotharine was marketed as Aleudrin in Germany

1946:  Swedish physiologist and pharmacologist Ulf von Euler (1905-1983) discovered that norepinephrine (noradrenaline) not adrenaline (epinephrine), was the sympathetic transmitte responsible for sympathetic messages to be sent from the nerve ending to the effector site (smooth muscle, heart or vessel).  This is yet another method by which the sympathetic nervous system works. The idea that neurotransmitters worked in this was was postulated in 1905, only to be proved by von Euler.  He won the Noble prize with fellow scientists working with chemical transmitters Julius Axelrod and Bernard Katz.  (2,4,5)

1948:  Working with the research of van euler, Raymond Ahlquis (1914-1983) discovered that there are various types of receptor cells used by the sympathetic nervous system.   Beta 2 adrenergic receptors (B2) were discovered to line smooth muscles that wrap around air passages in the lungs.  When these receptors were stimulated these smooth muscles relaxed, and this dilated the air passages to make breathing easeir  Since this discovery, rescue medicine is sometimes referred to as beta-2 agonists, beta adrenergic agonist, or simply beta agonists. (2)

Alquist also discovered the following: (2)
  • Alpha Affect:  noradrenaline is stronger than adrenaline is stronger than isoprenaline
  • Beta Affect:  isoprenaline is stornger than adrenaline is stronger than noradrenaline (3)(4)
The idea here is that the "flight or fight" response initiates the adrenal gland to release epinephrine, which attaches to B2 adrenergic receptors and causes the bronchioles to dilate.  Beta adrenergic medicine (such as epinephrine) can mimic this response.  So such medicine that mimic the sympathetic system in this way are called sympathomimetic agents.  . 

The terms Beta 1 Adrenergic (B1) and alpha-1 adrenergics (A1) are also described by Raymond Ahlquis.  A1 and B1 receptors line smooth muscles in the heart and that wrap around vessels, and when stimulated the heart rate increases in rate and force.  Epinephrine was found to be attracted to B1, B2 and A1 receptors.  So this explained why the instant breathing relief came with cardiac side effects.  The quest was now on to create a drug that had a strong B2 effect without the B1 and A1 effect.

Isopretoronol was learned by Raymond Ahlquist to have a stronger B2 effect than epinephrine, yet it also had a strong B1 effect that caused the heart to speed up "even when administered via inhalation."  So Isopretoronol still had to be used with discretion. (2)

1951: Iseotharine was approved by the FDA and marketed as Bronkosol.   It became yet another option via the nebulizer route, although, like epinepherine, it only lasted one and a half to two hours. It was the first B2 specific rescue medicine to hit the market.   It had a stronger beta effect and less of an alpha effect.  It was marketed as the first B2 specific inhaled aerosolized bronchodilator.  Bronkosol had less of a B2 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.  (2)

1954:   It should be noted here that Alquists experiments were initially rejected by many of his peers.  It wasn't until 1954, when he was invited by Victor Drill to write a chapter in Pharmacoloy in Medicine, that his ideas were accepted.  So, thankfully, "Ahlquist took advantage of the opportunity to promote his theory, which ultimately enabled it to gain general acceptance. The concept not only prompted fresh thinking about adrenergic receptor pharmacology, it also vaulted scientific research into new directions that would guide future drug development." (4)

1957:  The first metered dose inhaler hits the market.  Riker Pharmaceuticals introduced the Medihaler-Epi and the Medihaler-Iso which had epinephrine and isoprotoronol respectively.  For the first time ever asthmatics had a handy little inhaler to carry with them wherever they went.  The medicine provided instant relief from an asthma attack without the hassle of hunting down a doctor, or dealing with fragile and complicated nebulizers, solutions and hand held squeeze bulbs.  I wrote about this in more detail here.

Further reading:
Click here for more asthma history.

  1. Brenner, Barry E, ed., "Emergency Medicine," 1998, from chapter one "Where have we been?  A history of acute asthma," page 23
  2. Rau, Joseph L., "Inhaled Adrenergic Bronchodilators: Historical Development and Clinical Application," at (American Association of Respiratory Care, July, 2000, Vol. 45, number 7),
  3. Pang, Humphrey P., Maureen M. Dale, James M. Ritter, Rod J. Flower, Graeme Henderson, "Rand and Dale's Pharmacology," 2012, Esevier Churchill Livingstone
  4. Rubin, Ronald P., "A Brief History of Great Discoveries in Pharmacology: In Celebration of teh Centennial Anniversary of the Founding of the American Socieity of Pharmacology and Experimental Therapeutics," Pharmacological Reviews, December, 2007, vol. 59, no. 4, pages 289-359 (This article provides a good history of the discoveries of the sympathetic nervous system, the neuromuscular synapse, and how hormones such as adrenaline work)
  5. "Ulf on euler Biography (1905-1983),",, acessed 3/9/13

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