How Do Dual PDE-3/PDE-4 Inhibitors Work?

Dual PDE-3/PDE-4 Inhibitors are a novel class of medications used in the treatment of chronic obstructive pulmonary disease (COPD). Dual PDE-3/PDE-4 Inhibitors block two different enzymes to improve COPD symptoms by airway dilation (bronchodilation), and by reducing inflammation and mucus production in the lungs and airways.

COPD is a progressive condition usually due to smoking and/or air pollution, with symptoms such as coughing, wheezing, shortness of breath, chest tightness and excessive phlegm. COPD is associated with two main conditions, emphysema, in which the lungs’ air sacs (alveoli) are damaged, and chronic bronchitis where constant inflammation in the airway lining produces excessive mucus, making breathing difficult.

Phosphodiesterase enzymes (PDE) are a group of enzymes that regulate cellular levels of signaling molecules called cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), by breaking them down. Among the PDE enzymes, PDE-4 breaks down cAMP, and PDE-3 breaks down both cAMP and cGMP. These signaling molecules are responsible for activating many cellular functions.

Dual PDE-3/PDE-4 Inhibitors block the activity of both PDE-3 and PDE-4 enzymes, which increases the cellular concentration of cAMP and cGMP, enabling many downstream signaling effects. Increase in cellular levels of cAMP and cGMP in the lung tissues relieves COPD symptoms and protects the lungs from further damage in the following ways:

• Reduces inflammation in the lungs and airways
• Reduces scar tissue formation in the lungs, a cause for lung tissue damage
• Reduces mucus production and its viscosity, and helps in clearance of phlegm 
• Relaxes the smooth muscles around the airways, which results in bronchodilation and improved airflow
• Relaxes the smooth muscles around the pulmonary blood vessels, which dilates them and improves blood circulation to the lungs

Until now, medications used to treat COPD only inhibited PDE-4. Currently, the first-in-class dual PDE-3/PDE-4 inhibitor known as ensifentrine inhalation suspension, has been approved by the FDA on June 26, 2024 for maintenance treatment of COPD in adults. The drug has direct effect on the lung tissues because it is inhaled.

Dual PDE-3/PDE-4 Inhibitors are suspensions that are inhaled orally directly into the lungs with the use of a jet nebulizer that converts the solution into a fine mist of droplets. The dual PDE-3/PDE-4 inhibitor, enfensitrine is the first and only drug in this class approved by the FDA for the maintenance treatment of COPD in adults.

Common side effects of dual PDE-3/PDE-4 Inhibitors include the following:

• Back pain
• High blood pressure (hypertension)
• Urinary tract infection
• Diarrhea
• Paradoxical bronchospasm
• Psychiatric side effects including:
• Insomnia
• Anxiety
• Depression
• Adjustment disorder with depressed mood
• Suicidality

Information contained herein is not intended to cover all possible side effects, precautions, warnings, drug interactions, allergic reactions, or adverse effects. Check with your doctor or pharmacist to make sure these drugs do not cause any harm when you take them along with other medicines. Never stop taking your medication and never change your dose or frequency without consulting your doctor.

Generic and brand names of dual PDE-3/PDE-4 Inhibitors include:

• ensifentrine inhaled
• Ohtuvayre