1941: Dr. Christie defines emphysema and how to treat it

Ronald V. Christie was considered to be the most renowned expert on emphysema in the 1930s and 1940s.  He defined the disease pretty much as we know it today, and then he provided various treatment recommendations that he determined would help these patients during episodes of acute dyspnea.

In his article "Emphysema of the lungs:  part II," (British Medical Journal, Jan. 29, 1944, pages 143-146) he describes how ephedrine was the best medicine to relieve dyspnea.  He noted the following:

"Although there may be no evidence of bronchospasm or resistance to respiration, the administration of ephedrine not infrequently relieves the dyspnoea of emphysema.  A possible explanation of this effect is that the bronchioles leading to the over-distended air sacs and bullae are less capable of changes in calibre than those leading to healthier parts of the lung; bronchospasm, although not clinically manifest, would in this case increase the proportion of the inspired air deflected to these useless parts of the lung, and the relief of bronchospasm with ephedrine would improve the efficiency of ventilation and thus relieve dyspnoea."

It's interesting that he wrote this considering I have often wondered myself why a bronchodilator would benefit emphysema patients.  It's not like a bronchodilator would help a patient regrow lung tissue.  Yet what he wrote makes sense, and other more recent studies have confirmed what he suggested (sort of).

He briefly mentioned surgical procedures to deflate parts of the lungs.  He was also among the first to describe "respiratory exercises designed to teach the patient to deflate the lung and to increase the use of the diaphragm."

During the end stages of the disease when heart failure occurs he recommends oxygen.  Back then oxygen tanks had to be hauled into the hospital room by the nurse.  He explained that "recovery from heart failure in emphysema was uncommon."  However, he explained a case in which supplemental oxygen could extend the life of a "moribund" patient for a little while.

1679, 1814: The terms emphysema and bronchitis are coined

The 42-year-old Alaskan woman sat by the crackling fire 1,600 years before the birth of Christ.  She was severely winded after just a short walk with the children.  Her chest heaved up and down, occasionally interrupted by a dry, hacking, painful cough.

"I can no longer do  this," she decided, working hard to stop the tears.  The children stood around her silent and concerned.  These episodes were happening more frequently now, so often that she could barely stand it.  "I'm fine," she said.  It was a lie.

Looking into our prism we can see the woman obviously suffered from Cronic Obstructive Pulmonary Disease (COPD), although back then the disease she suffered from was poorly understood. In Alaska there may have been no treatment at all other than rest.

We know she probably acquired the disease gradually over time as she continued to inhale smoke from the same fires she used to cook food for the children and their parents.  We know she probably died slowly from lack of oxygen.

Nearly 1,600 years later, a Greek physician named Hippocrates described asthma for the medical community, describing it as dyspnea, or shortness of breath.  He was not aware of different causes of dyspnea, so they were all included under his umbrella term asthma.

Yet somewhere, tucked nicely under this umbrella, were patients who had inhaled some microscopic substances, perhaps a chemical, that caused changes of some airway tissue and destruction of others.  The end result were diseases we now refer to as chronic bronchitis and emphysema, and that we lump under the umbrella term chronic obstructive pulmonary disease.

It would be another 2,000 years before emphysema would be described around 1650 A.D.  The 17th century was well known as a time when physicians were performing autopsies in order to match symptoms observed in life with changes that occurred within the body.

Emphysema became a term that would be used to describe lungs that were larger than normal due to the fact they held abnormal amounts of air.  The term would come from the Greek term physe, which means "to blow into."  They did not, however, understand why the lungs had extra air blown into them, so this resulted in much speculation.

Theophile Bonet (1620-1689)

So it was in the year 1679  that a Swiss physician named Theophile Bonet performed over 3,000 autopsies on patients he followed, and was among the first to describe emphysema as a medical condition of "voluminous lungs" in his book Sepulchretum. (2) (3) (4)

Giovanni Morgagni (1682-1771) wrote how he respected the works of Bonet, and he himself described several cases of "turgid" lungs in his classic work "On the seats and causes of disease."

In 1784 Dr. Samuel Johnson was a well known physician, and he also became well known for his breathing trouble. He was thought to have suffered from asthma from birth, and later he was determined to have died of fibrosis of the lungs.  Although from autopsy results future historians have concluded that what he died of was emphysema and cor pulmonale and not asthma.  (6)

Dr. James Arthur Wilson was only 19 when he performed the autopsy on Dr. Johnson, and he described the following:

Dr. Samuel Johnson

"On opening into the cavity of the chest, the chest did not collapse as they usually do when the air is admitted, but remained distended, as they had lost the power of contraction; the air cells on the surface of the lungs were also very much enlarged... the heart was exceedingly large and strong."

In 1721 Ruysh provided the first detailed description of emphysema coupled with pictures.

Matthew Ballie was a prominent British physician who inherited his father's anatomy school in 1783.  Throughout his career he studied the bodies of diseased patients, including some specimens handed down to him, such as the lungs of Dr. Samuel Johnson.

Matthew Ballie (1761-1823)

In 1799 and 1807, Ballie  described emphysema with detailed pictures.  He described the condition as "enlarged air spaces" in the lungs, and lungs that did not collapse.

He published a book in 1793, "The Morbid Anatomy of Some of the Most Important Parts of the Human Body." It's believed to be the first book on pathology.

He described the lungs of emphysema patients, which included the following description of Dr. Johnson's lungs:

"The lungs are sometimes, though I believe rarely, formed into pretty large cells to resemble the lungs of an amphibious animal. Of this I have seen three instances. It is not improbable that this accumulation (of air) may break down two or three contiguous cells into one, thereby, form a cell of very large size." (5, page 2)

Charles Badham (1813-1884)

In 1814 British Physician Charles Badham became the first to use the term "bronchitis" to denote "inflammatory changes in the mucous membrane." (9?)

Bronchitis would soon "supercede" the term chronic catahrr when referring to chronic inflammation of the respiratory tract that resulted in a chronic cough and the spitting up of yellow or otherwise colorful phlegm.   (9)

Catahrr was a blanket term used to describe swelling of mucus membranes that resulted in excessive secretions. Throughout the remainder of the 19th century, catahr would continue to be used to describe inflammation of the nasal passages. Another term that caught on around the 1820s was or hay fever.  The terms allergy and colds would not be coined for another 80-plus years. (9)

Laennec accurately described emphysema (13)

In 1821 Dr. Rene Laennec -- known as the father of chest medicine in part due to his invention of the stethescope -- accurately described both emphysema and bronchitis as related conditions. (3)

He defined bronchitis as "chronic mucous catahrr," and "filled with mucous fluid."  (3)

He defined emphysema as "lungs (that) do not collapse.  But they fill up the cavity completely on each side of the heart."  (3)

Laennec became the first to describe emphysema due to aging, and he was the first to define emphysema as tissue damage in the peripheral air passages.  He further defined emphysema as a breakdown of tissue in the parynchema of the lungs as opposed to air trapped in the alveoli due to an obstruction such as occurs in asthma and bronchitis.

In this way, it was Laennec who became the first to distinguish chronic bronchitis and emphysema as separate entities from asthma.  He was the first to speculate that they ought to be extricated from the umbrella term asthma, to become disease entities of their own with their own treatments.

William Stokes (1804-1878)

In 1837 Dr. William Stokes became the first to use the term "chronic bronchitis" in his book "The Diagnosis and Treatment of Diseases of the Chest."  He defined bronchitis as "inflammation of the mucous membrane," and that this condition may give rise to "dilations of the air cells and tubes, and to pulmonary emphysema."  (8, page 45)

He also said bronchitis is evident in nearly all diseases of the lungs.  In noting this, he was drawing a similarity with bronchitis, pneumonia and asthma.

Like Laennec, Stokes was among the first to explain the relationship between chronic bronchitis and emphysema, and believed bronchitis lead to emphysema. He was also the first to describe different types of sputum, such as mucoid and mucopurulent.  (1, page 86).

He also mentioned increased secretions and chronic cough as part of the condition.

John Hutchinson's spirometer

In 1846 John Hutchinson invented the spirometer.  While he believed his device was limited in its purpose, it would become the perfect device for diagnosing and treating many diseases of the lungs.

His device was limited in that it could only measure vital capacity, which is the total amount of air that can possibly be exhaled. Yet this measurement would become useful in helping a physician distinguish between bronchitis, emphysema and asthma.

In 1861 Dr. Henry Hyde Salter described in his book, "On Asthma: It's Pathology and Treatment," that he had never performed an autopsy on an asthmatic when he didn't see evidence of emhysema.  Other doctors would make similar statements.  Salter also described the barrel chest common with asthmatic children.

However, Salter and other physicians of his day didn't have the ability to differentiate from true asthma as we know it today and true emphysema and chronic bronchitis.  Yet to their credit, emphysema was a rare disease until after WWI when cigarette smoking became common place.

By 1870 emphysema and chronic bronchitis were clearly noted as related diseases, and descriptions were present regarding the breakdown of lung tissue that resulted in progression of the disease that resulted in hyperinflation of the lungs. 

In 1885 a physician by the name of Mendelssohn "stated that he had met many persons dying from tuberculosis whose symptoms never showed themselves until they worked with coal dust and smoke." (10)

He was therefore among the first to observe the relationship between environmental inhalents and lung disease.

By 1898 the air sacs in the lungs were no longer called simply "cells," they were referred to as alveoli in books and magazines such as The Clinical Review. (12)

Emphysema was now clearly defined as "dilation of the alveoli of the lungs and atrophy of the alveolar walls."  (12)

Doctors such as Joseph M. Patton started differentiating overdistention of alveoli due to obstructive diseases such as asthma with excessive air in the lungs due to tissue "atrophy." (12)

By 1930 a plethera of descriptions of the conditions started to show up.  One physician described enlarged goblet cells in bronchitic lungs that resulted in increased secretions.   Another performed tests that showed airflow limitations in patients with emphysema, and explained that this was due to lost of lung elasticity.

By the 1930s emphysema was clearly understood to be a disease of loss of elasticity of the lungs that results in enlargement of the thoracic cage, which resulted in the appearance of a barrel chest, such as what was previously described by Salter. (11)

Because the chest was already expanded, the regular muscles of inspiration would be of little use in drawing in more air.  So, in order to take a deeper breath, the patient would have to make a conscious effort and use his accessory muscles.  At first these muscles would become sore, although over time, as they were used with increased frequency, they would become strong, and therefore hypertrophied, and would therefore be no longer sore.  (11)

In 1933 Ronald V. Christie, a professor of medicine at the University of London who specialized in emphysema, performed a study that showed the relationship between loss of lung elasticity and airflow limitations.  (1, page 87) 

With breakdown of tissue of the alveolar walls excess air enters this space and the result is overdistention.  This can also result in bulla, which are large areas of tissue breakdown and air trapping, meaning this entire portion of the lung will not be involved in the process of ventilation.  The end result is increased dyspnea.

In 1944 Christis suggested, that because the lungs were always expanded due to loss of elastic recoil, expiration would have to be passive.  He said:

"With loss of elasticity there must be loss of elastic recoil, so that if the lung is to be deflated it has to be squeezed. The respiratory musculature was not built for this task, and the intercostals have to be assisted by the accessory muscles on expiration: the muscles of the abdominal wall can often be felt to contract on expiration, which is prolonged as it is in other conditions, such as asthma and tracheal obstruction, in which the lungs have to be compressed by an active muscular effort. With so extensive an impairment of both inspiration and expiration it is not surprising that the vital capacity and chest expansion are reduced." (11)

In other words, he is describing the conscious use of accessory muscles.

He describes lungsounds as faint except for in the bases where they may appear to be absent.  Diagnosis could be made by observation of the physical signs, such as a barrel chest, vital capacity measurements with spirometry, and obvious dyspnea on exertion not attributable to other conditions.

He also suggested diagnosis should be made based on signs of chronic cough or asthma, meaning dyspnea.

By the 1950s physicians had learned so much about the lungs that they pretty much wiped the slate clean and redescribed both emphysema and chronic bronchitis for the medical community.

Experts determined there were various disease processes that could result in excessive air in the chest or overdistention of the alveoli such as acute asthma or chronic bronchitis. This "overdistention" was no longer considered emphysema. True emphysema would now be considered air in the interstitial spaces due to breakdown of parychemal lung tissue such as the pores of Kahn and the walls of the alveoli. 

Air trapping in asthmatics was determined to be completely reversible, and air trapping in chronic bronchitis patient only partially reversible.  As with emphysema, both may result in a barrel chest, although a barrel chest in asthma is only temporary, and the barrel chest in emphysema is chronic.

During the 1960s and 1970s pulmonary function testing was used with increased frequency to study lung diseases, and it was during this era that the term FEV1 was first used to measure expiratory flow. This is a test result that could not be faked, and that could easily be used to differentiate asthma from chronic bronchitis, emphysema, and other lung diseases.

By the 1980s pulmonary function testing would become commonplace in diagnosing COPD, with the measurement of FEV1 being the most significant measurement.

While physicians like Dr. Wilson keenly observed the large heart in those suffering from lung diseases, by the 1980s physicians understand that diseases like chronic bronchitis and emphysema, now lumped under the umbrella term COPD, became still.

In an effort to force blood through stiff lungs, the right heart is overworked and becomes enlarged over time, resulting in a condition called cor pulmonale. Physicians now understood that when this occurred, the disease was in it's final stages, or end stages.

It was at time time dyspnea would become increasingly worse, and might be caused by infections such as pneumonia in the lungs, or it might be caused by heart failure.

In 1972 the mummy of a 1,600 year old woman was discovered in Alaska. The woman was found to have evidence of emphysema, and this may be the oldest reported case of COPD.  (1, page 85).

1. Qutayba Hamid, Joanne Shannon, James Martin, "Physiologic Basis of Respiratory Disease," 2005, Montreal, page 85-99
2. Bhatia, K. Sujata, "Biomaterials for Clinical Application," 2010, London, page 100
3. Petty, Thomas L, "The History of COPD,"Int. J. Chron. Obstruct. Pulmon. Dis., 2006, March; 1(1): 3-14
4. Crellin, J. M.D., "Selected Items from the history of pathology," Am J Pathol. 1980 January; 98(1): 212.
5. Thurlbeck, Wright, "Thurlbeck's Chronic Airflow Obstruction," 1999, Canada, pages 1-6
6. Reich, Jerome M, "Convulsion of the lung: an historical analysis of the cause of Dr. Johnson's fatal emphysema," Journal of the Royal Society of Medicine, Vol. 87, December, 1984, page
7. Laennec, Rene, "Treaties of the diseases of the chest," 1821
8. Stokes, William, "The Diagnosis and Treatment of Diseases of the Chest," 1837, Dublin
9. Gee, Samuel, "Bronchitis, Pulmonary Emphysema and Asthma, " The Lancet, March 18, 1899, page 51
10. Klotz, Oskar, Wm. Charles White, ed., "Papers on the Influence of Smoke on Health,"  Bulletin #9, 1914, page 36
11. Christie, Ronald V, "Emphysema of the Lungs: Part II, British Medical Journal, Jan. 29, 1944, page 143-146
12. Cleveland, Geo. Henry, "The Clinical Review: AJournal of Practical Medicine and Surgery," Vol. VIII, April-Sept. 1898, Chicago.

Photos:  

1. http://library.medicine.yale.edu/about/adopt/laennec

It pays to be friends with your asthma doctor

Another advantage of having asthma is you get to move right to the front of the line.  Fifteen years ago when I called my doctor I got in right away, no questions asked:  all I had to do was say, "My asthma is acting up."  

Fast forward ten years, and having not made an unscheduled visit in 14 years (a record that shatters the old record by a whopping 14 years) and the secretary at my doctor's office completely ignores my call.  The conversation went something like this:

Me:  "Hi, I need to schedule an appointment."

Sec:  "Who's your doctor?"

Me:  "Dr. Mumbles

Sec:  "What's your problem?"

Me:  "Trouble with my asthma."

Sec:  "I'm sorry, but he's booked for the day."

Me:  "Well, how about tomorrow."

Sec:  "He'll be out of town."

Me:  "How about anytime this week."

Sec:  "No, he's out all week."

Me:  "How about one of the other doctors.  I'll see any one."

Sec:  "None of them are available either."

Me:  "So you're telling me I'm shit out of luck."

Sec:  "Yes."

So at least she was honest.  

The good news is I was sitting in the RT Cave while this phone conversation took place.  Five minutes later Dr. Mumbles came in and sat down next to me to interpret EKGs.  

I said, "Dr. Mumbles, I was wondering if you could do me a favor."

He picked up the phone, called his secretary, and got me on the schedule.  So if having trouble breathing isn't enough to get through the doctor's screens (his secretary), it pays to be friends with the doctor.  

Asthma clings to you wherever you go

I found a good quote that pretty much describes the life of the asthmatic:

And even in the intervals of health the asthmatic's sufferings do not cease:  he seems well, he goes about like his fellows and among them, but he knows that he is altogether different from them; he bears about his disease within him wherever he goes; he knows he is struck -- "haeret lateri lethalis arundo;" he is conscious that he is not sound -- he cannot be warranted; he is not certain of a day's, perhaps not of an hour's health; he only knows that a certain percentage of his future life must be dedicated to suffering; he cannot make an engagement except with a proviso, and from many of the occupations of life he is cut off; the recreations, the enjoyments, the indulgences of others are not for him; his usefulness is crippled, his life is marred; and if he knows anything of the nature of his complaint, he knows that his sufferings may terminate in a closing scene worse only than the present."  Henry Hyde Salter.

Source:  Salter, Henry Hyde, "On Asthma: It's Pathology and Treatment," 1882, New York, page 2

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Note:  "haeret lateri lethalis arundo," is Latin.  Translated into English it means "in her side still clings that deadly shaft."  Or, worded another way by eudict.com:  "The deadly arrow sticks in her (his) side."  Asthma is like the deadly arrow that clings to her side wherever she goes.  Asthma clings to you no matter where you go, no matter what you do.  It's always there hovering over you like a dark, ominous cloud.  

According to http://www.proz.com, it comes from Virgil's Aenid (book 4, string 73):

Sick with desire, and seeking him she loves, From street to street the raving Dido roves. So when the watchful shepherd, from the blind, * Wounds with a random shaft the careless hind, * Distracted with her pain she flies the woods, Bounds o'er the lawn, and seeks the silent floods, With fruitless care; for still * the fatal dart Sticks in her side *, and rankles in her heart.

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30,000 B.C.: The birth of allergies

Surely allergies have been around since the beginning of human existance.  Dr. Paul M. Ehrlich explained one theory in which allergies are believed to be "a leftover survival tactic" whereby ancient people living along the Tigris and Euphrates Rivers where repeatedly exposed to harmful germs such as bacteria and parasites.  (1)

Ehrlich said that back then, perhaps as far back as 30,000 years before the birth of Christ, our immune systems needed to be powerful to fight off these germs.  The people with the strongest immune response survived while others died.  "So," he said, "being an allergic person may have been an advantage." (1)

Yet today we have many defenses against such invaders, such as shoes, clothing, clean drinking water, processed food, vegetables that are treated with pesticides, air conditioned buildings, etc.  We receive vaccinations and use hand sanitizers.  People today simply aren't exposed to germs, so the allergic response isn't needed.

For most of us, our immune systems have adapted to the change.  Yet for some of us our immune systems continue to work overtime.  Lacking harmful germs to occupy our immune systems, they become bored and develop a sensitization to things that are supposed to be safe, such as dust mites, pollen, molds, and cockroach urine.

So this is the basis of why about 10 percent of the world's population develop allergies.

The rest of my history of allergies will be published on this blog in April of 2014.

For a complete history of allergies and asthma click here.

References:

1. Ehrlich, Paul M., Elizabeth Shimer Bowers, "Living with Allergies," 2009, page 6

History of the great bronchodilator Ephedrine

A long, long time ago -- three thousand years be exact -- in a land far, far away and isolated from the rest of the world by mountains, water, and a huge wall, sat a shirtless boy leaning forward in a crouched position, arms pressed against the floor supporting his shoulder's high.  With each breath his shoulders were sucked in, skin drawn taught.

A elderly man proffered a cup to the boy.  "Drink this, my son."

The boy frantically grabbed the cup from the elderly man and eagerly drank between gasps for air.  The drink was yellow; the taste bitter.  Yet he drank up knowing it was worth it. Within moments his heart was racing and pounding in his chest. Soon thereafter he could inhale a quarter of a breath, and then a full breath.  It felt so good.

This was life for lucky asthmatics who lived around 1500 B.C. in Ancient China.  A plant called Ma-Huang was used to treat a variety of ailments, especially breathing trouble.  Ancient Chinese asthmatics were lucky because this remedy was the most effective in all the ancient world for treating asthma.

While ephedrine and it's medicinal uses were described as far back as 6,000 B.C, credit for the first use of the herb was reported in ancient China.  Legacy has it that about 2700 B.C Chinese Emperor Shen Nung tasted hundreds of herbs to test their medicinal value, according to U.S. National Library of Medicine. 

One of the herbs he's believed to have tasted was ma huang.  It was listed in a medical book believed to be written by Shen called Shen-nung pen ts'ao ching (Divine Husbandman's Materia Medica).  This book listed 265 medicines, their doses, how to prepare them, and their uses.  Yet while Shen is given credit as the author, the true author (or authors) is unknown, according to U.S. National Library of Medicine.

Ma Huang became a classic remedy in Ancient China as a diaphoretic (it made you pee, which is good if you have fluid in your lungs making it hard to breathe), heart stimulant, antipyretic (it reduced fevers), cough reducer, nasal decongestant useful for colds and other breathing disorders such as asthma (although it wasn't called asthma by the ancient Chinese). 

Ma Huang is a product of a plant we now refer to as Ephedra Seneca, which is a shrub that reaches 60-90 cm high with a green, slender and somewhat flexible stem that is ribbed and channeled.  The stems are removed and beaten to separate them, and then they are dried in the sun.  A bitter tasting yellow powder is produced that is soluble in water, so it was often mixed with tea. 

Over 50 varieties of the species are available around the world, and it's indiginous to subtropical desserts and mountainous regions such as America, Europe and Asia.  Ephedra is also available in other unrelated plants such as sida cordifolia, according to Monchair S. Ebadi in his book "Pharmacodynamic basis of herbal medicine (2007, page 312)

Tea was a common drink of the Ancient Chinese, and rumor had it that Emperor Shen Nung was boiling water one day and a tea leaf landed in the pot.  He drank it and loved the flavor.  So Nung made popular both the asthma remedy and the tea to which it was delivered.  However, Ma Huang could also be eaten or smoked.

The plant Ephedra gerandiana grew in India and Pakistan.  The stems were cut, beaten, dried and used to treat various diseases.  Ephedra edistachya and Ephedra evulgaris were available in Europe, and there are recordings of the Russians using Ephedra for respiratory disorders and rheumatism, according to Steven B. Karch, in his book "Karch's Pathology of Drug Abuse," (Florida, 2009, page 241).

Pliney the Elder, who was Roman author from 23-79 A.D., wrote about Ephedra and it's medical uses.  Pliney wrote a lot about asthma, and it's possible he may have prescribed Ephedra as one of the remedies to help people breathe better.  So Ephedra was available to the Ancient Romans. 

Karch described that in the 1600s Native America Indians and Spaniards in the American Southwest used ephedra derived from the plant Ephedra nevedensis.  Only they used the plant to alleviate urinary incontinence and venereal diseases such as syphilis. 

Settlers in the American West, Karch wrote, brewed ephedra teas that were referred to by a variety of names including yellow tea or chaparrel.  When the Mormon's arrived in Utah they were introduced to Ephedra tea by local Indian tribes, and this is one reason it's often referred to as Mormon tea. 

While ephedra was used by various societies, and continued to be used even up to modern times by the Chinese, it was not introduced into the West until 1885 when Yamanashi isolated the active ingredient.  A few years later in 1887 Nagayoshi Nagai isolated an alkaloid in Ephedra vulgaris, which is a genus of the plant that grows in Europe. 

Nagai gave this alkaloid the name ephedrine and is given credit by history for it's discovery.  A few years later another chemist also isolated it.  Nagia and others did extensive studies on the alkaloid and discovered that it's a stimulant for the central nervous system, and circulatory system.  It was also found to dry secretions, and was effective for runny eyes and runny noses, or as a nasal and chest decongestant.  It was also proven to be a dilator of smooth muscles that wrap around the lungs and gastrointestinal tract.

While not commonly known, ephedra was actually the best asthma treatment until 1901 when adrenaline was discovered. If communication was what it is today thousands of years ago, asthmatics wouldn't have had to suffer for so many years.  In fact, even while ephedrine was being used in the West to treat asthma in 1901, it didn't hit the market until 1926.

Karch describes how representatives for the pharmaceutical company Merck followed Nagia's research closely hoping to add this new medicine to the market and profit from it, and it did so.  But the product they produced didn't sell well and the products were all but abandoned until 1926 when Chen and Schmidt read a report they wrote about the alkaloid and it's uses to the Section on Pharmacology and Therapeutics.

Chen and Scmidt described ephedrine as a top line asthma medicine. They actually believed ephedrine was as effective as epinephrine, yet it was later learned this was not true. 

After Chen and Scmidt's report sales of ephedrine skyrocketed so fast that there was concern demand would top supply.  So the march was on to find if a synthetic ephedrine (this means it can now be produced in a factory and is called racemic ephedrine) could be produced.

While ephedrine was synthesized that same year, the ephedrine shortage never occured.  The medicine was then approved by the American Medical Association as a bronchodilator that was safer to use than epinephrine, and was later available as an over the counter option.  Racemic ephedrine was marketed under the name Ephetonin.

By the 1930s ephedrine -- like epinephrine -- was available by either injection or hand held nebulizer, according to Greg Mitman in his book, "Breathing Space" (London, 2007, page 232).  By 1954 it was available as an over the counter medicine and marketed as an asthma remedy and nasal decongestant.

The ephedrine solution was called ephedrine sulfate. 

Pseudonephrine is another alkaloid derived from ephedra plants, only it's cardiac effect was much less than ephedrine.  For this reason pseudinephrine was marketed as an over the counter nasal decongestant.  A common brand is sudafed.

Popular ephedrine product available as an over the counter remedy in the 1960s were Franol and Franol Plus (which also contained theophylline, a bronchodilator, to ease breathing), according to Mark Jackson in his book "Allergy:  The History of a Modern Malady" (London, 2007, pages 126 and 127).

Jackson wrote that Franol was a combination of ephedrine, theophylline and a barbituate and was marketed as an asthma, bronchitis and hay fever remedy.  Franol plus was the same with the addition of an antihystamine for those also suffering from allergies. 

Other alkaloids discovered from ephedra plant and similar in structure to ephedrine and pseudonephrine are amphetamines and methamphetamines.  The affects of these alkaloids are similar to cocaine, in that they stimulate the central nervous system, boost metabolism, decreases appetite, and enhance performance.  They can create euphoria if used in high doses, can be addicting, tolerance can build up over time, and overdosing can result in cardiac side effects including death. Long term use can result in heart muscle damage and death. 

In the rush to create a synthetic ephedrine in 1927 it was discovered how to turn ephedrine into ampthetimines and methamphetamines.  Sales of ephedra products skyrocketed in the 1990s as the medicine was used as a weight loss product and as a performance enhancer by athletes.  Abuse of the medicine resulted in several reported deaths (although some experts doubted ephedrine was the cause).

Another reason sales spiked in the 1990s is people learned how to make amphetamines and methamphetamines out of over the counter pseudonephrine and ephedrine products.  This abuse encouraged the Food and Drug Administration to ban over the counter sales of the ephedra in 2004, and pseudonephrine products are still available but are monitored closely by pharmacists.

Ephedrine is really no longer needed as a nasal decongestant nor as an asthma remedy as far better and safer treatments are now available.  In fact, it's usefulness waned years before it was banned as an over the counter medicine. 

Yet if your physician believes you'll benefit from this medicine it's still available as a prescription, and it's not illegal if you posses it.  It's rarely prescribed, however.

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