Tuesday, March 27, 2012

Theophylline no longer top line asthma medicine

In 1976 my pediatrician started prescribing Sustair, a liquid theophylline to control my asthma.  I remember my mom feeding me that stuff with a teaspoon, and it tasted nasty.  For the next 30 years I was chronically dependent on theophylline, although ultimately I was able to take the pill version called Theo-Dur or some generic version.

In his 1807 book, "A practical inquiry into disordered respiration: distinguishing the species of convulsive asthma, their causes and indications of cure," Dr. Robert Bree recommended coffee as one of the best remedies for asthma, and listed various physicians who likewise recommended it. 


For example, he wrote that "Sir J(ohn) Floyer used it with great benefit in the later part of his life, as appears from the account of Dr. Musgrave."  (1)

In the 1860s Dr. Henry Hyde Salter wrote a book, "On Asthma," and he recommended strong coffee and tea to help control hardluck asthma.  He believed sleep favored asthma and coffee helped keep you awake.  (2) With Salter as his doctor, this was a remedy occasionally tried by a young asthmatic Teddy Roosevelt.  (3)

Salter may have known coffee was a member of the xanthine family, but he probably didn't know xanthines are mild bronchodilators (they dilate the air passages in your lungs).  This wasn't proven until 1921, and by 1922 theophylline suppositories were used to treat asthma. The name is derived from the Greek root theo meaning tea and phyllon meaning plant.

Theophylline is an alkaloid -- a white, crystalline powder -- that was first derived from tea leaves (Camellia sinensis) in 1888.  It was first recommended as an asthma remedy by the Ancient Chinese in about 1000 B.C.  It's similar to caffeine and theobromine in its effect.

Caffeine was first isolated in 1812 and theobromine in 1841.  Caffeine is an alkaloid most commonly found in coffee beans and tea leaves, and theobromine an alkaloid from the cacao plant which is used to make cocoa and chocolate. 

All Xanthines have an effect on the central nervous system in that they, improve mental acuity, and act as mild bronchodilators and diuretics (makes you pee).  Caffeine has a stronger effect than theobromine and theophylline has a stronger effect than caffeine.

When theophylline was first discovered it was used as a diuretic for patients with heart failure to help remove excess fluid buildup (edema) in the lungs and ankles, according to Tora Navarra in her book "The Encyclopedia of Asthma and Respiratory Disorders" (New York, 2003, page 188).  In 1900 theophylline was synthesized (meaning it could now be made in a factory).

It wasn't until 1922 the bronchodilating effects of theophylline were discovered. How it causes bronchodilation is relatively a mystery, although it's believed to block the release of adenosine which causes bronchoconstriction.  It's also believed to strengthen contractility of the diaphragm to reduce fatigue, according to Navarra.  It's a respiratory stimulant.

Amimophylline was another methylxanthine discovered in 1922.  It has similar bronchodilating effects as theophylline, only it's more soluble in water and more suitable as an intravenous medication.  Aminophylline was first used in 1937.

Theophylline and aminophylline were available for use on asthmatics in the 1930s, and were basically the only effective alternative to epinephrine.  Yet use of these medicines didn't take off until the 1950s when they were approved for use on asthmatics, and by the 1970s theophylline was a top line asthma medicine.  (Again, it generally takes about 10-20 years for new ideas in medicine to catch on).

By this time theophylline was usually prescribed as a bronchodilator to control and prevent asthma at home, and aminophylline was prescribed in hospitals to be administered intravenously. If you were admitted to a hospital with asthma between 1950 and 1990, chances are you had aminophylline running in your IV at some point. 

Aminophylline was originally recommended for asthma not responsive to epinephrine, yet once Alupent and later Albuterol were discovered to be as effective as epinephrine for most asthmatics -- and safer too, aminophylline was reserved for asthmatics in the hospital who were not responding to other therapies.

Antihistamines hit the market in 1946.  This is a type of medicine that blocks the effects of histamine, which is a mediator of inflammation released during the allergic response that causes swelling and redness (inflammation) that results in the allergic response of itchy eyes and throat, stuffy and runny nose, and sneezing.

In 1947 Hydrallin hit the market.  This was a white tablet that contained both an antihistamine (25mgm of Benadryl) to treat allergies and a bronchodilator (aminophyllin 100 mcg) to relax the air passages*.  This became a popular prescription medicine for asthmatics, and later an over the counter medicine.  It was removed from the shelves in 1981.

I know from my medical records I was given aminophylline during many of my admissions for asthma. As I wrote above, theophylline was prescribed for me at an early age to help control my asthma long term.  Along with asthma, theophylline is a top line drug for chronic bronchitis and emphysema patients too.

The problem with theophylline was that it had a very narrow therapeutic level.  Too low and it didn't do anything, yet too high there were toxic effects.  Back then 20 was considered toxic, meaning the medicine might cause vomiting, ceizures and even death.  There were a few times when I became extremely nauseated and had to miss school, and in retrospect wonder if I overdosed on theophylline. 

Most side effects, though, are generally mild.  Some are similar to when you drink coffee, such as irritability, insomnia, nervousness and jitters.  Since Xanthines are also mild diuretics, it might cause you to pee more.  It can also irritate the lining of your stomach, much like drinking too much coffee could do this.

Another thing ingestion of too much xanthines can do is cause your esophageal sphincter to relax, and this may result in gastrointestinal reflux (GERD).  As we now know, GERD in itself can trigger and even cause asthma.  It's for this reason coffee is on the antireflux diet prescribed for anyone with heartburn or acid indigestion. 

Still, while there were side effects to theophylline, it was deemed to be much safer than being on systemic steroids to control asthma. It was also better than suffering from asthma.  So as with any medicine, the risks had to be weighed against the potential benefits.  For me, the benefits far outweighed the risks. 

Another problem with this drug is it only lasted in your system 4 hours, so I had to take it every 8 hours or my levels dipped in the middle of the day causing asthma symptoms.  When I was at the asthma hospital in 1985 I had a 24 hour theophylline study done, and had to have my blood drawn every few hours.  It wasn't so bad, though, because they put a line in my hand to draw from.

Greg Minton, in his book "Breathing Space: How Allergies Shape Our Lives and Landscapes," (2007, London, page 237) wrote that in the early 1980s sustained-released theophylline was introduced to the market.  By 1985 sales of this product, according to Minton, reached up to 25 percent of all prescription medicines prescribed for asthma.  Immediate and sustained release theophylline made up "50 percent of all prescriptions written for asthma drugs."


Before I was at the asthma hospital I was introduced to Slo-Dur, which is a long acting theophylline and allowed me to only take one pill a day. Yet my doctors at the asthma hospital frowned on me taking this.  Their thinking was that my levels would dip between doses, exacerbating my asthma.  So the first thing they did when I was admitted was take me off Slo-Dur and put me back on Theo-Dur.

In this way, sustained released theophylline was ahead of it's time (kind of like the Pacer).  Many established doctors refused to accept it as a top line asthma medicine.  Yet by the late 1990s sustained released asthma medicine became ideal asthma medicine because it reduced the need to remember to take your medicine at various times during the day, and this greatly improved compliance taking asthma medicines, which ultimately improved asthma control in itself.

Yet that wisdom would come later on down the history line.  At this time -- in 1985 at the asthma hospital -- I was taking 300mg of theophylline in the morning and before bed.  The results of the study showed my level dipped in the middle of the day, so my new regime had me adding a 300mg dose around 2 p.m.  This sucked because I now had to think about taking pills all day.

This medicine was one of the first bronchodilators to be released long term in the bloodstream, and this meant it only needed to be taken once or twice a day.
As you can see I had become chronically dependent on this medicine.  If I skipped a dose my lungs would itch and sputum production would increase.  I'd ultimately go into an asthma exacerbation that was not reversible with bronchodilators.  The only remedy was to get my theophylline level back up to therapeutic levels, which back then was considered to be between 15 and 20.

In 2002 my doctor at that time told me the normal dose he prescribes is 300mg twice a day.  Yet the dose I was on at that time was 600mg twice a day, and somehow that still kept me under the toxic level.  (I wonder how many cups of coffee that's equivalent to.)

In the early 1980s theophylline was determined to be "less efficacious" than anticholinergic medicines like Atropine when it comes to dilating bronchioles, yet it wasn't until the 21st century that theophylline faded away as a top line asthma drug. 

Many doctors were staunch defenders of this medicine because it worked so well for them for so many years.  I was a staunch defender of it because my body became dependent on it to the point that when I forgot to take a pill I would have the worse asthma attacks ever.

Perhaps some of my fellow asthmatics will empathise with me.  A good example of this was when I forgot to take my theophylline for three days when I was busy in college in 1988.  Absent this bronchodilator my lungs freaked out.  My chin became itchy, my chest burned, and my mucus production increased almost to the point I felt I might choke.

 
My room mate Frank walked in on me and I must have been a sorry sight all frogged up on the edge of my chair, grunting with each expiration, tears in my eyes, misting nebulizer clipped between my teeth.

 "You look like you're gonna die."

"Give me ten more minutes," I grunted, "If I still look like I'm going to die, drag me to the ER."  Feeling helpless I'm sure, he stood by and watched as I suffered.



I was so familiar with these pills I could pick them out in the dark by feel

Then, right on cue, I felt the mucus letting up; the chest tickling feeling letting go, and my breath coming back.  First came a quarter breath, then a half a breath five minutes later, and finally... "Ahhhhh, man it feels good to breathe." 

All in all, it took about 30 minutes from popping that little white pill for my breathing to be back to normal.

When I was really little and this happened I'd go to the ER, but at some point in my asthmatic life I learned the difference between a regular asthma attack and one induced by a low theophyllin level.
The Albuterol treatment was useless during one of these attacks, however I always took one.  
"NO!" I insisted.  I had just popped a Theo-Dur pill dry.  I knew from past experience it would take about 20 minutes before my breath started coming back."NO!  I'll be fine," I grunted."Do I need to take you to the ER," he said.

That's why I was such a staunch defendant of this medicine, and was upset when Theodur was no longer made, and I had to swallow generic theophylline horse pills instead. I feared the medicine would no longer be available, and I'd die as a result. 

In December of 2007 I approached my doctor about getting off theophylin, and he said, "It's neat you bring this up, because when I started as a doctor nearly every one of my asthma patients was on theophylin, and now your one of only two."

In the past Theophylin was a top line bronchodilator usually used in conjunction with inhaled corticosteroids.  New long term bronchodilators with fewer side effects have replaced theophylin, two are called Advair and Symbicort. 

In 2005 my doctor recommended I try Advair.  In the summer of 2006 when I traveled to Detroit to visit my brother and forgot my theophylline pills I was panicked.  I thought I'd have a bad asthma attack.  Yet it didn't happen.  I think the reason is because the medicine in Advair (serevent and flovent) kept my lungs from spasming.  I did have some spasming in my lungs, but not enough to make me uncomfortable.  In fact, this may have been more psychological than actual.  Still, this made me think that it might just be possible to get off this medicine I once figured I'd be on for life. 

At my next appointment my doctor said, "You've been on theophylin so long, and it seems to work so well for you, I'd hate to tinker with it."

"One attempt, doc" I said.  "I just want to make one last attempt at getting off it.  If it doesn't work, it doesn't work."

We decided on a very, very, very, very, very slow wean.  In fact, the wean took a full year to complete.  And it worked.  On January 31, 2007, I took that last pill.  And, just in case (as if in tribute to an old friend), I left an unopened prescription bottle of theophylin in the medicine cabinet just in case

Once upon a time I thought I would never get off that dreaded theophyline.  Now every time I open the medicine cabinet and see that bottle of theophylin pills, I'm reminded of the importance of continued asthma research.

Today what to do with theophylline is still being debated. New evidence shows it's also an antiinflammatory and works better than leukotriene inhibitors like Singulair.  So the future of theophylline is still up in the air. Although at present it's rarely used.  I also used one of those old theophylline pills to end an asthma attack recently, so having some on hand might be a good idea too.

So while Teddy Roosevelt guzzled cups of coffee praying it would help him catch his breath, scientists gave asthmatics theophylin in the 1950s.  Now, with even greater advancements in asthma medicine, theophylin is no longer a top line asthma medicine.

(For a doctor's perspective on theophylin click here).
*Menace, Bernard A, "A Clinical Evaluation of Hydrallin and Trimeton (Tripoton) in Allergic Manifestations," Canad. M.A.J., August 1949, vol. 61, page 156. 

References:

  1. Bree, Robert, "A practical inquiry into disordered respiration: distinguishing the species of convulsive asthma, their causes and indications of cure," 1810, London, page 293
  2. Salter, Henry Hyde, "On Asthma: It's Pathology and Treatment," 1860, 
  3. McCullough, David, "Mornings on Horseback," 2001, New York, pages 93-111

3 comments:

  1. I was on theophylline from 2006 to 2010. I got off for about a year and then I ended up having to go back on it to get better control. It was either add that or keep needing prednisone on a pretty regular basis. I am at a higher dose then I used to be, but it does help a lot.

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  2. It's a good medicine, and remains a viable option for those who need it. I still pop a pill once in a while to end some of my tougher asthma attacks in lieu of going to the ER. Great medicine. I pray they don't some day decide to stop making it.

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  3. I have taken Theodur for the past 20 years. Once in a while I will go a few days without taking it, but always go back to it. It really does help me breathe and along with Advair and a rescue inhaler, I have my asthma under control.

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