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100 PharmacyTimes.org December 2015 ments in diagnosis of the disease, as well as a steady improvement in median sur- vival. 2 Until the 1980s, patients with CF usually succumbed to respiratory failure during childhood. 3 Although the median age at death is still approximately 27 years, the median age of survival in the United States was 40.7 years in 2013, an improvement of more than 8 years since 1998. 2 The disease affects many organ sys- tems in addition to the lungs. As first described on an autopsy in 1938, the pan- creas has a characteristic cystic appear- ance, and destruction and fibrosis leads to pancreatic insufficiency in nearly 90% of patients. 2 Many have poor weight gain or experience steatorrhea or other gastrointestinal (GI) symptoms, which require pancreatic enzyme replacement therapy. Hepatic involvement, cholesta- sis, and CF-related diabetes often occur in patients as they age and require addi- tional therapy. 4 The improvement in treatment options over the years has resulted in a shift in demographics, as well as the disease. The number of patients with CF attending college and attaining an undergraduate or a graduate degree has increased over the past decade. 2 The number of pregnancies among women with CF has also contin- ued to rise over the past 2 decades. 2 In terms of the disease itself, pul- monary complications remain a major source of morbidity and the primary cause of mortality, 5 but the microbiol- ogy has changed substantially over time. Staphylococcus aureus, methicillin- sensitive Staphylococcus aureus, and Pseudomonas aeruginosa remain the most common pathogens infecting the lungs of patients with CF. 2 Although the promi- nence of P. aeruginosa has decreased since 1998, other strains that were neg- ligible before have strikingly increased. These include methicillin-resistant S. aureus (MRSA), Stenotrophomonas maltophilia, mycobacterial species, and multidrug-resistant P. aeruginosa, all of which were detected in less than 5.5% of patients in 1998, and can now be seen in 25.6%, 13.7%, 12.1%, and 9.2% of patients, respectively. 2 As the life expectancy of patients with CF increases, so does the complexity of the disease, complications of CF, and the treatment regimens needed. The most common complications reported include gastroesophageal reflux disease (31.3%), sinus disease (30.7%), asthma (26.3%), CF-related diabetes (20.3%), osteopenia (11.2%), and depression (12.3%). 2 The increase in comorbid conditions associated with CF requires health care practitioners to effectively manage these conditions and the associated polytherapy required, including the complexity of the treatment regimen for CF. The treatment options available for patients with CF have increased substantially in the past decade. To tailor treatment regimens for individual patient needs and optimal treatment man- agement, health care professionals need to appreciate the underlying pathobiology of CF, the mechanism of action of the treat- ment options available, and the interplay of these complex new regimens. Pathobiology of CF and the Role of CFTR Pathobiologic phenotypes in CF begin with a mutation at a single gene locus on the long arm of chromosome 7, which codes for the CFTR protein, 1480-amino acid polypeptide. 6 CFTR acts as a cyclic adenosine monophosphate (cAMP) dependent chloride channel in the apical membrane of epithelial cells lining the lungs, sinuses, pancreas, intestines, vas deferens, biliary tree, and sweat ducts. 6-8 Mutations in the CF gene cause CFTR to malfunction, resulting in pathophysi- ologic alterations in salt and water trans- port on epithelial surfaces in the airways. This defect makes patients with CF espe- cially vulnerable to chronic endobronchi- al infections, 8,9 which, along with luminal obstruction and chronic inflammation, can lead to progressive airway obstruc- tion and declining pulmonary function. 6,10 Defective CFTR function also influ- ences expression of several other cell functions, such as apical sodium trans- port, that modify the CF phenotype and contribute to inflammatory responses, maturational processing, and cell signal- ing. 6,9 Ultimately, mutations in the CFTR gene result in gross malfunction and structural pathology in key organs, such as the lungs, pancreas, and liver. 2,11 Almost 2000 mutations of the CFTR gene have been reported and are grouped into 6 classes based on their known functional consequences. 1 Class I and II mutations result in impaired delivery of CFTR mutations to the cell surface: Class I through truncated protein translation, and Class II through mis- folded CFTR. Class III and IV mutations reduce the function of CFTR proteins at the cell surface through gating defects or impaired conductance, respectively. 12 Similar to Class I and II, Class V and VI mutations also reduce the quantity of functional CFTR proteins: Class V through mutations that affect mRNA stability and Class VI through mutations that impact CFTR stability. 13 Mutation of the CFTR gene by deletion of phenyl- alanine at position 508 (F508del) is the most common, responsible for approxi- mately 66% of all CF chromosomes. 2 Pathogenesis of Lung Disease CF is characterized by an impairment in the normal process of bacterial clearance by inefficient mucus transport, which is caused by an accelerated rate of epi- thelial sodium absorption coupled with poor chloride secretion. 9 The impaired mucociliary clearance results from dehy- drative reduction of the periciliary air- way surface liquid volume and lays the foundation for persistent bacterial infec- tion through a variety of pathogens that have a predilection for the CF airway. 8 This reduction leads to dramatic reduc- tions in ciliary movement in the airway, which makes clearance of secretions extremely difficult. The inflammatory response is characterized by an excessive and persistent infiltration of neutrophils into the airway—one of the hallmarks of CF. 10 Mutations resulting in the absence or dysfunction of CFTR result in an ionic imbalance that manifests itself as thick dehydrated mucus secreted in several organ systems, most notably the respi- ratory system. 13 Mucosal obstruction resulting from CFTR dysfunction is the primary contributor to disease progres- sion in CF, contributing to the unre- mitting cycle of bronchial obstruction, infection, and inflammation that results in the progressive decline of respiratory function in patients with CF. 6,10 What are the major drug therapy treatment options for the man- agement of pulmonary exacerba- tions and GI manifestations of CF? CONTINUING EDUCATION STAR