O2.2 Phosphodiesterase type-4 inhibitors

Inhibitors of phosphodiesterase type-4 (PDE-4) act by increasing intracellular concentrations of cyclic adenosine monophosphate and causing a range of anti-inflammatory effects.

Two drugs, cilomilast and roflumilast, have been developed, but neither has been approved for use in Australia or New Zealand at this time. Placebo controlled studies up to six months duration (Rennard et al., 2006),(Rabe et al., 2005) have found that PDE-4 inhibitors attenuate decline in lung function and quality of life, and decrease acute exacerbations when compared to placebo [evidence level II].

PDE-4 inhibitors significantly increase the FEV₁, by an order of 40 - 100ml, compared to placebo. They improve quality of life, measured by the SGRQ total score, by 1.6 - 4.1 units compared to placebo, but the changes did not reach statistical significance in all studies. PDE-4 inhibitors significantly reduced acute exacerbations, whether measured by the mean number of exacerbations or exacerbation-free survival. Placebo controlled RCTs have now been extended to 52 weeks.(Calverley et al., 2009) They confirm a consistent improvement in pre-bronchodilator FEV₁ and a 17% reduction in the annual rate of exacerbations with roflumilast. The effects on lung function, exacerbations and breathlessness are additive to those of long acting bronchodilators such as salmeterol and tiotropium(Fabbri et al., 2009)[evidence level II]. Drug related adverse effects mainly affected the gastrointestinal system; diarrhoea, abdominal pain, nausea and vomiting and weight loss and were approximately twice as common in subjects taking PDE-4 inhibitors as in those taking placebo.

PDE-4 inhibitors are promising candidates for the treatment of chronic obstructive pulmonary disease. Further research is required to determine their long-term impact and role when used with other treatments including glucocorticoids and long-acting bronchodilators.