Roflumilast: First Phosphodiesterase 4 Inhibitor Approved for Treatment of COPD.

Roflumilast: First Phosphodiesterase 4 Inhibitor Approved for Treatment of COPD.

Anas.M

Fifth Year Pharm D Student, Dept of Pharmacy Practice.

Al-Shifa College Of Pharmacy

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Roflumilast Roflumilast is an oral, once-daily selective phosphodi­esterase-4 inhibitor with a broad range of action against inflammatory cells playing a major role in COPD. It decreases swelling in the lungs. It was approved by CDSCO in 2013 for use as concomitant maintenance treatment of severe COPD along with  bronchodilators in patients with frequent exacerbations in the past. Roflumilast is not a bronchodilator and is not indicated for the relief of acute brochospasm.

COPD is a progressive, irreversible lung disease. Symptoms of COPD include breathlessness, chronic cough and excessive Sputum production. A significant worsening of symptoms - called an    exacerbation-can last several weeks and often requires substantial medical intervention, including hospitalization. The prevalence of chronic obstructive pulmonary disease (COPD) has been increas­ing over the last few decades and is a leading cause of morbidity and mortality worldwide. It was the sixth leading cause of death in 1990 and is expected to be the third leading cause of death by 2020. Acute COPD exacerbations are a leading cause of hospitalizations, associated with US $29.5 billion in direct costs. The Global initia­tive for chronic Obstructive Lung Disease (GOLD) guidelines state that the strongest predictor for future exacerbations is a history of previous exacerbations.

One novel class of compounds that may deliver therapeutic benefit in COPD are phosphodiesterase (PDE) 4 inhibitors. PDE is a generic term that describes a large super family of enzymes that catalyze the breakdown of cyclic adenosine-3’, 5’-monophosphate (cAMP) and/or cyclic guanosine-3’,5’-monophosphate (cGMP) to their respective inactive nucleotide 5’-monophosphates. Eleven distinct PDE families have been identified, though most of the anti-inflammatory activity is believed to result from the inhibition of PDE4, for which there is clinical precedent.In April 2010, the European Medicines Agency Committee for Medicinal Products for Human Use recommended approval of roflumilast, a selective phosphodiesterase 4 inhibitor, for the “maintenance treatment of severe chronic obstructive pulmonary disease (COPD, FEV1 post bronchodilator less than 50% predicted) associated with chronic bronchitis in adult patients with a history of frequent exacerbations as add-on to bronchodilator treatment”.Selective phosphodiesterase (PDE)-4 inhibitor; PDE-4 inhibition leads to accumulation of intracellular cyclic adenosine monophosphate (cAMP) in lung tissue.Roflumilast 500 mcg daily improve lung function and reduced exacerbations in patients with more severe COPD, especially those with chronic bronchitis, frequent exacerbations, or who required frequent rescue inhaler therapy. It is contraindicated in patients with severe liver impairment and hypersensitivity. Belongs to pregnancy category C. Indeed,  Theophylline is a weak, nonselective PDE inhibitor and has been used in clinical practice as a bronchodilator for more than 70 years.

Daliresp is the first and only selective phosphodiesterase-4 (PDE4) inhibitor approved and is an oral tablet taken once daily with or without food. Advantages of roflumilast over inhaler therapy are that it is an oral tablet and only needs to be taken once daily.Roflumilast tab and its combination with Salmeterol was approved by CDSCO in 2013 and got approval for marketing in india from june 2014, as a treatment to reduce the risk of chronic obstructive pulmonary disease (COPD) exacerbations in patients with severe COPD associated with chronic bronchitis and a history of exacerbations. Roflumilast is not a bronchodilator and is not indicated for the relief of acute brochospasm.

Mechanism Of Action

·         Roflumilast inhibits PDE4, which lead to an accumulation of intracellular.   While the specific mechanism is not well defined, the therapeutic effect of Roflumilast is thought to be related to the effects of increased intracellular cAMP in lung cells.  

Mechanism Of Action Roflumilast