PDE4 Inhibitors and Methylxanthines

What are phosphodiesterase-4 inhibitors and methylxanthines?

Phosphodiesterase-4 inhibitors (called PDE4 inhibitors) and methylxanthines are two types of medication that may be used to treat people with chronic obstructive pulmonary disease (COPD).

People with COPD have airways that are irritated and inflamed. This can make them too narrow for enough air to pass in and out of the lungs. Sometimes, this irritation can cause the band of muscles that surrounds the airways to tighten up, which makes the airways become even narrower. This is called a bronchospasm. Bronchospasms often happen during acute exacerbations, or COPD flare-ups.

Medicines called bronchodilators are often used to help relax the band of muscles around the airways and make it easier for COPD patients to breathe. Corticosteroid medicines work by reducing the amount of swelling in the airways and making it easier for air to pass through.

When bronchodilators and steroids are not able to relieve COPD symptoms, some patients may need to use other types of medicines to manage their disease, such as PDE4 inhibitors and/or methylxanthines.1-3

How do PDE4 inhibitors work?

PDE4 inhibitors work by helping to reduce swelling in the airways in a different way than corticosteroids do. This can be helpful for people who cannot tolerate corticosteroids due to the side effects. PDE4 is a type of enzyme that is involved in the inflammatory response. In people with COPD, there is too much inflammation in the airways, which can make it difficult to breathe. PDE4 inhibitors block the enzyme and can help reduce the inflammation.2

The only PDE4 inhibitor that is currently approved to treat COPD is called Daliresp® (roflumilast). It is swallowed by mouth in a pill that is taken once a day, every day. Patients are usually prescribed a bronchodilator to use in combination with Daliresp. For patients with severe COPD, Daliresp can help to reduce the number of acute exacerbations they have per year.2,4

PDE4 inhibitors such as Daliresp cannot be used to treat severe or sudden COPD symptoms. It is a maintenance therapy that needs to be taken regularly every day to reduce the number of flare-ups a patient has in the long term. It cannot be used to treat a flare-up once it has started, like bronchodilators or corticosteroids can. It is only used to help reduce the number of attacks that will happen.2,4

What are the possible side effects of PDE4 inhibitors?

The most common side effects experienced by people taking PDE4 inhibitors include:

  • Diarrhea
  • Weight loss
  • Nausea
  • Headahce
  • Back pain
  • Dizziness
  • Decreased appetite
  • Flu-like symptoms
  • Difficulty sleeping (insomnia)5

For many patients, these side effects go away after they have been taking a PDE inhibitor for a while. Patients should consult with their healthcare providers if they have any of these side effects that are severe or do not go away.

PDE4 inhibitors may cause severe side effects, including suicidal thoughts or behaviors. People experiencing suicidal thoughts, an increase in depression or anxiety, or other unusual changes in behavior or mood should seek medical attention.5

How do methylxanthines work?

In the past, methylxanthines were a common treatment for COPD. The way they work is not exactly understood, but their effect is to reduce swelling in the airways and relax the bands of muscles around them. The most common type of methylxanthine is called theophylline.1,3

Methylxanthines are not used very often anymore, because they are not as effective as the newer kinds of bronchodilators. Also, they can cause serious side effects for some people. However, methylxanthines can be another treatment option for COPD patients who do not get enough symptom relief from other types of bronchodilators.1,3

What common side effects are linked to methylxanthines?

It is important to be very careful about taking the correct amount of a methylxanthine medicine. Taking too much methylxanthine can cause very serious side effects. Taking other types of medicines at the same time as theophylline can also make side effects more likely.1

The most common side effects experienced with methylxanthines include:

  • Nausea
  • Diarrhea
  • Headache
  • Stomach pain
  • Restlessness
  • Irritability
  • Difficulty sleeping (insomnia)6

Several more serious side effects can also be caused by methylxanthines, including:

  • Vomiting
  • Irregular or rapid heartbeat
  • Seizures
  • Skin rash6

Patients should seek medical care right away if they have any of these serious side effects of methylxanthine treatment.

Written by: Anna Nicholson and Emily Downward | Last reviewed: April 2018.
View References
  1. Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Lung Disease, 2018 Report. Global Initiative for Chronic Obstructive Lung Disease (GOLD). Available at http://goldcopd.org/wp-content/uploads/2017/11/GOLD-2018-v6.0-FINAL-revised-20-Nov_WMS.pdf. Accessed 4/3/18.
  2. Beghè B, Rabe KF, Fabbri LM. Phosphodiesterase-4 inhibitor therapy for lung diseases. Am J Respir Crit Care Med. 2013 Aug;188(2):271-8. doi: 10.1164/rccm.201301-0021PP.
  3. Vaz Fragoso CA. Role of methylxanthines in the treatment of COPD. UpToDate. Available at https://www.uptodate.com/contents/role-of-methylxanthines-in-the-treatment-of-copd. Accessed 4/3/18.
  4. Daliresp product website. Available at https://www.daliresp.com/. Accessed 4/3/18.
  5. Daliresp prescribing information. Available at https://www.azpicentral.com/daliresp/pi_daliresp.pdf. Accessed 4/3/18.
  6. Theophylline. MedlinePlus, U.S. National Library of Medicine. Available at https://medlineplus.gov/druginfo/meds/a681006.html. Accessed 4/3/18.