Wednesday, April 04, 2012

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.

3 comments:

  1. This comment has been removed by a blog administrator.

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  2. 60,000 BC seriously? That was before the last ice age.

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  3. Thanks. I made the correction.

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