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PHARM 311 Respiratory System > 11. Cystic Fibrosis > Flashcards

11. Cystic Fibrosis Flashcards

1
Q

Cystic fibrosis

A
  • 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
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2
Q

CFTR mutation defects - classification

A

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

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3
Q

Organs/areas of the body affected by cystic fibrosis

A
  • Lungs
  • Gastrointestinal tract
  • Hepatobiliary system
  • Pancreas
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4
Q

Lungs

A
  • Impairment to flow is due to bronchial plugging by purulent secretions
  • Bronchial wall thickening due to inflammation
  • Both lead to airway destruction
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5
Q

Medication targeting the lungs: Dornase alfa - Pulmozyme

A
  • 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
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6
Q

Medication targeting the lungs: Bronchodilators

A
  • Salbutamol (Ventolin, Respigen)
  • Dose: 1-2 puffs (100-200 mcg) up to QID
  • Side effects: Fine tremor, headache, tachycardia
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7
Q

Medication targeting the lungs: Hypertonic saline

A
  • 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
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8
Q

Antibiotics in cystic fibrosis

A

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
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9
Q

Bacteria & cystic fibrosis

A

Most common pathogens:

  • Pseudomonas aeruginosa
  • S. aureus
  • Methicillin-resistance S. aureus
  • Burkholderia cepacian complex

Other pathogen seen:

  • H. influenza
  • Streptrophymonas
  • Non-tuberculosis mycobacterium
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10
Q

Pseudomonas aeruginosa

A
  • 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
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11
Q

Staphylococcus aureus

A
  • 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
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12
Q

Burkholderia cepacia

A

Chronic infection is associated with an accelerated decline in pulmonary function & shortened survival in CF

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13
Q

Antibiotics

A
  • 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
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14
Q

Intravenous antibiotics

A
  • Aminoglycosides e.g. tobramycin, amikacin, gentamycin
  • Augmentin
  • Aztreonam
  • Ceftazidime
  • Colomycin
  • Meropenem
  • Piperacillin + tazobactam
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15
Q

Pharmacokinetics in CF

A
  • 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
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16
Q

Recap: Aminoglycosides

A
  • 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
17
Q

Aminoglycosides: TDM measurement points

A

Cmax (peak) – occurs 30 minutes post infusion after distribution in ECF
- Usually not measured as recommended OD, doses are&raquo_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
18
Q

Aminoglycosides: Resistance & ADRs

A
  • Limited resistance but use restricted by toxicity

- Resistance usually due to efflux pumps & degradation enzymes rather than ribosomal conformation

19
Q

Tobramycin - Dose, side effects, monitoring

A

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
20
Q

Ceftazadime

A

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

21
Q

Home IV antibiotics

A
  • 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
22
Q

Drug stability in infusers

A
  • 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
23
Q

Oral antibiotics

A
  • Amoxicillin
  • Augmentin
  • Ciprofloxacin
  • Clarithromycin
  • Co-trimoxazole
  • Flucloxacillin
  • Azithromycin
24
Q

Azithromycin

A

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

25
Q

Nebulised antibiotics

A
  • Tobramycin (most common)
  • Colistimethate (Colistin)
  • Gentamycin
  • Amphotericin (liposomal)
  • Aztreonam (liposomal)
26
Q

Antifungal treatment

A
  • Amphotericin (liposomal)
  • Fluconazole
  • Itraconazole
  • Voriconazole
27
Q

Gastrointestinal issues - constipation

A

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
28
Q

Hepatobiliary (liver & biliary) system

A
  • 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
29
Q

Drugs targeting hepatobiliary system

A

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)
30
Q

Pancreas insufficiency

A

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
31
Q

CFTR modulators: Ivakaftor

A
  • 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
32
Q

CFTR modulators: Lumacaftor-Ivakaftor

A
  • For patients with homozygous delta F508 mutation (~70% of patients)
  • Not available in NZ
  • FDA approved in July 2015
33
Q

Trikafta

A

Morning:
- Ivacaftor 75 mg + Tezacaftor 50 mg + Elexacaftor 75 mg

Evening
- Ivacaftor 150 mg

Must be taken with fatty food

34
Q

Vaccinations

A
  • Standard immunisation schedule

- Yearly influenza vaccine

35
Q

Pharmacist role in CF

A
  • 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

PHARM 311 Respiratory System (10 decks)

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