Cystic Fibrosis

Describe the epidemiology of CF

>10,400 people in UK. >90% of UK CF population is Caucasian. 1 in 25 people in UK are carriers. Every week 5 babies born with CF and 2 patients die. >50% live to at least 47 years old

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What is cystic fibrosis?

An intestinal and respiratory disease. Inherited genetic disorder affecting the gene for the protein CF transmembrane conductance regulator (CFTR). CFTR is a gated ion channel. Conducts Cl- ions out of cells. Subsequent effects on Na and H2O movement

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Outline the process of CFTR expression

Copy of CFTR gene made. Copy is read and translated into immature CFTR protein. Immature protein is modified, unique structure of channel forms. CFTR channel transported to the surface. Surface expression - CFTR channels become functional

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Describe the CF mutations (1)

I - production (no production of CFTR in DNA). II - transportation (CFTR read/build but can’t get to cell membrane to act as channel)

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Describe the CF mutations (2)

III - gating defect (channel opens/closes at inappropriate times). IV - conductance defect (pore of channel is not shaped correctly – cannot get transfer of ions). V - production (some production of CFTR)

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Describe the CF mutations (3)

VI - increased destruction (increased turnover of CFTR protein, down regulated too quickly, not enough time to act)

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Describe features of diagnosing CF

Can be - CF unlikely, non-classic CF or classic CF. Clinical features. Newborn screening. Scratch test. Sweat test (measure Cl concentration, 30-59 mmol/L is borderline and >60 mmol/L is confirmed CF)

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What are the effects of CF?

Chronic sinuits, nasal polyps, repeated lower respiratory tract infection, bronchiectasis, liver disease, abnormal sweating, pancreatic insufficiency, diabetes, osteoporosis etc.

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What is the effect of CF on the pancreas? (1)

Bicarbonate ions cannot be secreted from pancreas, destruction of pancreas due to bicarbonate build up, malabsorption, vitamin deficiencies, unable to absorb fats (leads to steatorrhea – oily fatty stools – could lose movement of bowels)

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What is the effect of CF on the pancreas? (2)

Pancreatic insufficiency occurs when losing >90% ability. Occurs in majority of CF patients (90%). Treated with PERT (Creon - contains lipase, protease, amylase)

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Describe features of Creon dosing (1)

Number of capsules taken based on amount of fat content in diet. Capsules need to be taken with food. < 10 g fat (1-2 capsules), 10-20 g fat (2-3 capsules). >20 g fat (4-5 capsules). No fixed dose. Babies need higher levels of lipase than adults

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Describe features of Creon dosing (2)

Dose based on weight for babies. Dose adjusted based on bowel movements, diet. Patients need to maintain high calorie diet to maintain their weight. Vitamin deficiency (lipid soluble)

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Describe features of vitamin A deficiency

Night blindness and xerophthalmia (cornea ulcerations/cloudiness can lead to blindness). Maintenance of epithelial cells. Worse clinical status - poorer prognosis, low weight, decrease in lung function/bone mineral density

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Describe features of vitamin D deficiency

Important for bone health. Rickets, osteopenia, osteoporosis. Need to maintain vitamin D content in CF patients

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Describe features of vitamin E deficiency

Neurological problems. Anaemia. Improves cognitive function. Controls progression of lung disease. Decrease effect of free radicals (formed from oxygenation). Decrease damage to cell membranes

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Describe features of vitamin K deficiency

Bone health. Production of osteocalcin is vitamin K dependent. Osteocalcin secreted by osteoblasts. Increase bone formation. Increase strength of bone. Not given if Hx of clots (controversy with use of warfarin/anti-coagulants)

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Describe features of vitamin replacement

Recommended daily doses - 8000 iu (vitamin A), 800 iu (vitamin D), 300 iu (vitamin E), 10 mg (vitamin K). Can use combination therapies (with calcium and colecalciferol)

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Describe the respiratory effects of normal lung function

The airway surface liquid (ASL) is a thin layer of aqueous fluid. Optimal depth is 7 micrometres. Allows cilia to fully extend and beat. Height and level of mucous hydration mediated by Na 2+ absorption and Cl- secretion (mediated by CFTR channels)

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Describe the respiratory effects of CF lung function (1)

Na 2+ reabsorption not down-regulated. Hyperabsorption of Na 2+. Subsequent absorption of water. Water comes from the ASL then the mucous. Consequences (increase surface dehydration, decrease mucociliary clearance, increase viscosity of mucous

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Describe the respiratory effects of CF lung function (2)

Allows accumulation of bacteria. Constant Na absorption, water follows (from ASL) – dehydrates ASL, cilia cannot work properly/cannot clear mucus and bacteria, build-up of bacteria (leads to inflammatory response, build-up of genetic junk)

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Describe the respiratory effects of CF lung function (3)

Also leads to scarring of lungs (lungs don’t functional as well)

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Give examples of mucolytics

Dornase Alfa nebs 2.5 mg od (Pulmozyme - first line). Sodium chloride 7% nebs 4 mL bd (Hypertonic Saline). Mannitol dry powder inhaler 400 mg bd (Bronchitol)

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What is the mechanism of action for Pulmozyme?

CF patients have excessive amounts of DNA fragments in their sputum. DNase is a recombinant deoxyribonuclease. Cleaves the DNA to decrease viscosity of the sputum

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What is the mechanism of action for Hypertonic Saline and Bronchitol?

Creates an osmotic gradient to draw water out from cells to rehydrate the airway surface liquid so that mucociliary function can be improved to help make sputum less viscous and expectorate

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What are the chronic pathogens present in CF patients?

Pseudomonas aeruginosa. Staphylococcus aureus. Haemophilus influenzae. Burkholderia cepacia complex (most serious - cannot have a lung transplant with this chronic pathogen/don't do well after transplant)

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What are the nebulised treatments for chronic P. aeruginosa?

Colomycin. Promixin (first line - better lung deposition, faster administration). Tobi and Bramitob. Cayston. Quinsair (levofloxacin - greater systemic absorption, more adverse effects)

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Describe features of treating respiratory exacerbations (1)

Antibiotic choice influenced by recent sputum cultures. Check allergy status. Check what they had before/number of recent exacerbations. Sensitivities not used to influence Tx. Higher doses used in CF patients

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Describe features of treating respiratory exacerbations (2)

(enhanced drug clearance, poor penetration into viscous, purulent sputum)

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What are the antibiotic choices for the organism pseudomonas?

Ceftazidime, meropenem, piperacillin/tazobactam, timentin, aztreonam, fosfomycin PLUS Tobramycin (1st line) , colistin (2nd line)

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What are the antibiotic choices for the organism cepacia?

Meropenem, temocillin, ceftazidime, co-trimoxazole

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What are the antibiotic choices for the organism achromobacter?

Meropenem, piperacillin/tazobactam, minocycline

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Describe features of other organisms - NTM (1)

Non-tuberculous mycobacteria colonise CF patients. Prevalence of 24%. M. Abcessus + M. Avium Complex (MAC). M.Abcessus associated with poorer outcomes. Initial IV regimen: Amikacin, Cefoxitin, meropenem, imipenem (three agents)

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Describe features of other organisms - NTM (2_

Treated for 18 months with - oral macrolide (Azithromycin/clarithromycin), 2 of the following: Minocycline, Linezolid, Moxifloxacin, nebulised amikacin OR meropenem

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Describe features of fungi (1)

Fungal infections (Aspergillus fumigatus most recognised). Leads to Allergic Bronchopulmonary Aspergillosis (ABPA). Scedosporium and Candida parapsilosis also problematic

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Describe features of fungi (2)

Treatment - prednisolone (ABPA), triazoles – itraconazole, voriconazole, posaconazole. Nebulised amphoteracin. IV amphoteracin, Caspofungin, Anidulafungin

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Describe features of CFTR modulators

Potentiators - correct gating mutations, hold channel open. Correctors - correct shape of CFTR protein, improves trafficking. Amplifiers - increase amount of CFTR protein made

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Describe features of ivacaftor

Potentiator, only modulator prescribed in UK. 9 mutations. Clinical trials - 11% increase in FEV1, rapid onset and sustained over 48 months, fewer pulmonary exacerbations, increased body weight, improved QOL scores

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Describe features of lumacaftor

Corrector, combined with ivacaftor. Heterogenous F508. Clinical trials - 3% increase in FEV1, marginal increase in body weight, similar number of exacerbations, rapid onset and sustained over 24 weeks - poorly tolerated

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What are the future therapies? (1)

Tezacaftor - corrector, hetero + homozygous F508, 7% increased FEV1, better side effect profile than lumacaftor. Next generation modulators - further improve CFTR folding/trafficking, target most common mutations, likely to be triple therapy.

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What are the future therapies? (2)

Amplifiers (PTI-428) currently in phase 1 trials. Inhaled ENaC blocker (P-1037) in phase 2 trials but hyperkalemia is an issue. Oligo G derived from seaweed, has antibacterial/mucolytic properties

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What are the future therapies? (3)

Read through agents - ataluren results in production of a full length CFTR, phase 3 trial underway, affected by inhaled aminoglycosides

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Cystic Fibrosis

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