May 31, 2011
By Trevor Shewfelt, Pharmacist at the Dauphin Clinic Pharmacy
A cup of coffee. Viagra. Being out of breath. A cigarette. Trouble getting dressed. When I think of these things I think of phosphodiesterase inhibitors.
Back in 1886 an asthmatic scientist named Henry Hyde Salter found that when he drank a strong cup of coffee on an empty stomach, his breathing got better. I was taught in pharmacy school that was because the caffeine caused adrenaline or epinephrine to open up the airways. That might not be the whole story. Caffeine has since been shown to be a weak, non-selective PDE inhibitor. Since 1886, chemical cousins of caffeine like theophylline have been successfully used to treat airway diseases like asthma.
PDEs or phosphodiesterases are enzymes in almost every part of your body. Different sub-types of PDEs are in different tissues. There seem to be at least 11 different sub-types of PDEs. One subgroup of PDEs are called PDE-5. It was found that certain PDE-5 inhibitors helped with the breathing of exercise induced asthmatics. Another PDE-5 inhibitor sildenafil relaxed blood vessels through the nitric oxide (NO) pathway. So sildenafil was originally tested as a treatment for angina. In angina, not enough blood gets to the heart muscle, so if we relax the blood vessels more blood will get through and the angina or chest pain will get better. Unfortunately, the tests showed sildenafil wasnt very good at treating angina. However, it turned out to relax blood vessels in the corpus cavernosum. This led to sildenafil to be know by its other name, Viagra. Viagra or sildenafil is an effective treatment for erectile dysfunction. The fact sildenafil relaxes blood vessels through the NO pathway is also why we say you cant use it with nitrates. Nitrates also cause blood vessel relaxation through the NO pathway, so sildenafil and nitrates together could cause an unsafe drop in blood pressure.
PDE-5 inhibitors can treat erectile dysfunction. PDE-5 inhibitors can also treat a specific heart condition called pulmonary hypertension. What about the rest of the PDEs? PDE-4 inhibitors have been studied since the 1970s. There was a drug called rolipram that blocked PDE-4 and increased norepinepherine in the brain. This made it an effective antidepressant, but it was associated with a lot of nausea and stomach trouble and was never brought to market. Remember caffeine weakly inhibits all the PDE enzymes. So caffeine might have some weak antidepressant activity. This could be part of the reason that many people with mental illness are also heavy users of caffeine.
A chemical cousin of caffeine called theophylline has been used for years to treat airway disease. Theophylline inhibits all the PDEs. Some of why theophylline works is thought to be its inhibition of PDE-4. That led to a lot research into chemicals that just inhibit PDE-4. One of these chemicals is called roflumilast or Daxas. As a PDE-4 inhibitor, roflumilast is thought to work by inhibiting many of the infection fighting cells in the body. Suppressing these infection fighting cells should reduce inflammation in the lungs in people with COPD.
COPD or Chronic Obstructive Pulmonary Disease includes emphysema and chronic bronchitis. It is most often caused by smoking. If you smoke as a young person you increase the chance you will get COPD in your later years. People with COPD have symptoms like coughing up phlegm and getting out of breath while getting dressed in the morning. I heard a doctor describe socks, underwear, pants, and t-shirt as the four piece COPD wardrobe. Putting on those 4 articles will take someone with COPD 20 minutes and then they will be exhausted and out of breath.
COPD will be the third leading cause of death worldwide by 2020. Unlike other chronic diseases like heart disease, COPD death rates are increasing. For example from 1965-1998 death rates from heart disease and stroke have decreased by about 60%. Death rates from all causes have decrease by about 7%. Death rates from COPD from 1965-1998 have increased by 163%.
In COPD, cigarette smoke damages the lining of the lung. This damage causes the infection fighting cells in the lungs to go into overdrive. The cigarette smoke makes them think the lungs are under attack. This leads to chronic inflammation in the lungs. This inflammation can lead to loss of flexibility in the lung tissue and more holes in the lungs. The inflammation leads to lots of mucus and phlegm in the lungs as well. So if we could reduce the inflammation in the lungs of COPD patients, they should breathe better. As a PDE-4 inhibitor, that is what roflumilast does.
Daxas or roflumilast is a 500 mg tablet and should be used once a day. It is expensive at up $90 per month. It is not covered by pharmacare as it is new. It shouldnt be the first medication your doctor gives you for your COPD. You should already be taking a short acting inhaler like salbutamol or atrovent, a long acting inhaler like tiotroprium and possibly a combination inhaler like Advair before your doctor will consider adding on daxas. Daxas is intended for people with severe COPD, who cough up a lot of sputum and have more than one severe exacerbations per year.
Daxas has had some interesting side effects reported as well. There was some increased risk of cancer reported in rats, but that hasnt been proven in humans. There are some worries about increased chances of suicide or suicidal thoughts on daxas. If you remember that a large number of people with COPD also have depression, and the number of people in the trials with suicidal thoughts was very low, it becomes less clear if Daxas is a cause of suicidal thoughts or not. It is interesting though, that the PDE-4 inhibitor rolipram that never made it to market in the 1970s was being looked at as an antidepressant.
The most common side effects of Daxas or roflumilast were diarrhea, weight loss, nausea and headache. The stomach issues usually went away after a couple of weeks on roflumilast and the weight that was lost came back after the roflumilast was stopped. Is roflumilast for everyone with COPD, no. But in a patient who has been maxed out on every other medication, it is an other tool in the tool box.
As always if you have any questions or concerns about these or other products, ask your pharmacist.
The information in this article is intended as a helpful guide only. It is not intended to be used as a substitute for professional advice. If you have any questions about your medications and what is right for you see your doctor, pharmacist or other health care professional.
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