11. Cystic Fibrosis Flashcards
Cystic fibrosis
- Multisystem disorder caused by mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene on chromosome 7
- Characterised by intermittent acute exacerbations, superimposed on a gradual decline in pulmonary function
- Effects many body systems other than lungs
CFTR mutation defects - classification
Class I – defective synthesis of full-length CFTR protein
- Few to no mature CFTR proteins are formed
Class II – defective CFTR protein processing & trafficking
- Defective post-translational processing & transport reduce quantity of CFTR protein delivered to cell surface
Class III – defective CFTR channel gating
- CFTR is at the cell surface but channel-open probability is reduced
Class IV – defective CFTR channel conductance
- CFTR is at the cell surface but has impaired movement of ions through channel
Class V – reduced synthesis of CFTR protein
- A splicing defect reduces quality of properly processed CFTR mRNA transcript, decreasing quantity of CFTR protein at the cell surface
Class VI – reduce stability of CFTR protein
- Accelerated turnover of CFTR protein at the cell surface reduces quantity
Organs/areas of the body affected by cystic fibrosis
- Lungs
- Gastrointestinal tract
- Hepatobiliary system
- Pancreas
Lungs
- Impairment to flow is due to bronchial plugging by purulent secretions
- Bronchial wall thickening due to inflammation
- Both lead to airway destruction
Medication targeting the lungs: Dornase alfa - Pulmozyme
- Indicated if FEV1 persistently <70% predicted despite optimisation of therapy
- Synthetic enzyme that cleaves neutrophil derived DNA in sputum to reduce viscosity
- Dose: 2.5 mg nebulised OD (at least an hour before next physio session to allow time to work
- Side effects: Dyspepsia, pharyngitis, dyspnoea, laryngitis
- Requires Special Authority or NPPA
Medication targeting the lungs: Bronchodilators
- Salbutamol (Ventolin, Respigen)
- Dose: 1-2 puffs (100-200 mcg) up to QID
- Side effects: Fine tremor, headache, tachycardia
Medication targeting the lungs: Hypertonic saline
- Used to encourage sputum production in patients > 6 years
- Can cause bronchoconstriction so pre-treatment with a bronchodilator e.g. salbutamol is recommended
- Usually followed by physic
Antibiotics in cystic fibrosis
Used in 3 situations:
- Eradication & delays of colonisation in early lung disease (treatment of positive cultures)
- Suppression of bacterial growth once colonised
- Reduction of bacterial load in acute exacerbations
Bacteria & cystic fibrosis
Most common pathogens:
- Pseudomonas aeruginosa
- S. aureus
- Methicillin-resistance S. aureus
- Burkholderia cepacian complex
Other pathogen seen:
- H. influenza
- Streptrophymonas
- Non-tuberculosis mycobacterium
Pseudomonas aeruginosa
- Cystic fibrosis airway are particularly susceptible to Pseudomonas with infection occurring as early as within the first year of life
- The prevalence of pseudomonas increases with the patients age
- Chronic infection is an independent risk factor for accelerated loss of pulmonary function & decreased survival
Staphylococcus aureus
- Bacterial pathogen most frequently identified in respiratory secretions of cystic fibrosis infants & children
- In children under 6 years of age infected with pseudomonas, co-infection with S. aureus has an independent & addictive effect on airway inflammation
- MRSA is being more prevalent
Burkholderia cepacia
Chronic infection is associated with an accelerated decline in pulmonary function & shortened survival in CF
Antibiotics
- Choice of antibiotic based on previous/current sputum cultures
- Prophylactic antibiotics not routinely used
- Poor penetration of antibiotics into the purulent airway
- Native or acquired antibiotic resistance
- CF related defects in mucosal defences
- Biofilms produced by the bacteria renders antibiotic ineffective
Can be given:
- IV
- Oral
- Nebulised
Intravenous antibiotics
- Aminoglycosides e.g. tobramycin, amikacin, gentamycin
- Augmentin
- Aztreonam
- Ceftazidime
- Colomycin
- Meropenem
- Piperacillin + tazobactam
Pharmacokinetics in CF
- Pharmacokinetics of many antibiotics differ in patients with CF compared to normal individuals
- Volume of distribution & total body clearance is increased for hydrophilic drugs such as aminoglycosides, penicillins & cephalosporins because CF patients are undernourished & have decreased adipose tissue
- Because of this higher or more frequent dosing is required for many patients
Recap: Aminoglycosides
- Gentamycin, tobramycin, amikacin (streptomycin, neomycin)
- Amino group bound by glycoside linkage to a central 6 membered ring
- Large molecule but smaller than vancomycin so penetrates Gram negative bacteria well
+ Positives charge facilitates transition through outer membrane by creating transient holes
+ Requires oxygen dependant transport through cytoplasmic membrane therefore poor anaerobic cover
+ Binds to 30S subunit causing mismatching of mRNA & tRNA leading to protein subunit mistranslation
Aminoglycosides: TDM measurement points
Cmax (peak) – occurs 30 minutes post infusion after distribution in ECF
- Usually not measured as recommended OD, doses are»_space;>MIC
4-6 hours post dose
- Used to calculate an AUC or draw the ADME curve using software
Cmin (trough)
- Offers little to no PK benefit
- Used to check for clearance & reduces risk of toxicity
Aminoglycosides: Resistance & ADRs
- Limited resistance but use restricted by toxicity
- Resistance usually due to efflux pumps & degradation enzymes rather than ribosomal conformation
Tobramycin - Dose, side effects, monitoring
Dose:
- Adults – up to 8 mg/kg OD
- Paediatrics – 10 mg/kg OD (max 600 mg)
- Infused over 30 minutes
Side effects:
- Nephrotoxicity, irreversible ototoxicity
Monitoring:
- Adults: SEBAGEN, NextDose
- Paediatrics: Trough level taken prior to 2nd dose (within 60 minutes)
- Should be < 1mg/L
- Repeat every 4-7 days while on treatment
Ceftazadime
Dose:
- Adults – 2 g Q8h
- Paediatrics – 50 mg/kg (max 2 g) Q8h
Note: NZF max 9 g in 24 hours (hydrophilic drug)
Side effects:
- Diarrhoea, nausea, vomiting, abdominal discomfort
No monitoring required
Home IV antibiotics
- For patients who are receiving planned regular antibiotics e.g. 2 week ‘tune up’
- First 5-7 days of antibiotics in hospital
- Patients or their caregivers are trained how to change infusers, care for the IV line
- Pharmacist orders infusers from Baxter
- Usually Ceftazidime & Tobramycin infusers
Drug stability in infusers
- To ensure that the patient is going to receive the prescribed dose over the 24 hour period
- Limited data for many antibiotics
- Take into account stability refrigerated & at room temperature
- UP BP specifications 95-105% of drug needs to be in solution to be stable
Oral antibiotics
- Amoxicillin
- Augmentin
- Ciprofloxacin
- Clarithromycin
- Co-trimoxazole
- Flucloxacillin
- Azithromycin
Azithromycin
Commonly used as an anti-inflammatory treatment taken 3 times a week
Proposed mechanism of action:
- May cause interference with pseudomonas biofilm production
- Have antibacterial activity during stationary growth
- Cause neutrophil inhibition & reduction in sputum viscosity
Side effects: GI, taste & smell disturbances, QT prolongation
Precautions: prolonged QT & used in combination with other QT prolonging drugs
Interactions: QT prolonging drugs, amphotericin B, diuretics
Potential for resistance
Nebulised antibiotics
- Tobramycin (most common)
- Colistimethate (Colistin)
- Gentamycin
- Amphotericin (liposomal)
- Aztreonam (liposomal)
Antifungal treatment
- Amphotericin (liposomal)
- Fluconazole
- Itraconazole
- Voriconazole
Gastrointestinal issues - constipation
Lactulose:
- Osmotic laxative
- Dose: 2.5-20 mL BD (age dependent)
- Side effects: Nausea, abdominal discomfort, cramps, flatulence
- Monitor for dehydration
Macrogol (Molaxole, lax-sachets):
- Dose dependent on age & response
- Usually ½ - 1 sachet BD/TDS
- Side effects: Abdominal distension & pain, nausea, flatulence
- Monitor for dehydration
Klean prep – acute constipation
- Often given via NG due to large volume required
- Each sachet is reconstituted with 1L of water
- Amount given depends on age/weight
- Start low & titrate up to a max of 4L over 4 hours
- Always done in hospital
Hepatobiliary (liver & biliary) system
- Patients who tend to have severe CF liver disease usually presents during childhood & the disease progresses rapidly
- Early identifications leads to better treatment of its complications such as malnutrition
Drugs targeting hepatobiliary system
Ursodeoxycholic acid:
- Dose: 10-20 mg/kg/day in divided doses
- Requires NPPA for funding
- Side effects: Diarrhoea
- Available as capsules or can be compounded into liquid by pharmacist
Fat soluble vitamin deficiency – Supplement with:
- Micel E (vitamin E)
- Vitadol C (for vitamin A content)
- Vitamin K
- Vitabdeck (contains A, B, C, D, E, K)
Pancreas insufficiency
Insulin:
- Dose: Dependent on requirements
- Type: Often use an intermediate acting with a short acting insulin e.g. Protaphane & Actrapid
- Side effects: Hypoglycaemia, local reactions & fat hypertropy at injection site
- Monitoring: Patients should be monitoring their blood glucose at least 3x daily
Pancreatin (Creon 10,000 or Forte)
- Dose: Based on fat consumption, take before or during a meal or snack
- For small children who can’t swallow capsules, open capsule & sprinkle on apple puree
CFTR modulators: Ivakaftor
- Used in patients with certain mutations in the CF transmembrane conductance regulator (CFTR) gene
- Improves the transport of chloride through the ion channels by binding to the channels directly
- Funded as of 1st of March 2020
- Costs ~$29,360 for 1 months’ supply
- Dose: 150 mg BD (>6 years)
- Taken with fat containing foods
- Side effects: GI, headache, dizziness
- Interactions
+ Metabolised by CYP3A4
+ Carbamazepine, rifampicin
CFTR modulators: Lumacaftor-Ivakaftor
- For patients with homozygous delta F508 mutation (~70% of patients)
- Not available in NZ
- FDA approved in July 2015
Trikafta
Morning:
- Ivacaftor 75 mg + Tezacaftor 50 mg + Elexacaftor 75 mg
Evening
- Ivacaftor 150 mg
Must be taken with fatty food
Vaccinations
- Standard immunisation schedule
- Yearly influenza vaccine
Pharmacist role in CF
- Medicine reconciliation on admission
- Monitoring of antibiotic levels where appropriate
- Appropriateness of antibiotic choice & dosing
- Identifying funding issues
- Ordering home infusers for discharge
- Liaising with DRs & Nurses for supply/funding of drugs
