Cystic Fibrosis

Classification

Most common life-shortening genetic disorder in Caucasians.
Genetic mutation in gene encoding CFTR protein - functions as a Cl channel

  • Moves Cl out of cells into airways
  • Na follows thus water follows
    = Keeps the moist and functional

Reduction/No CFTR function = less moist and less functional airways

  • viscous secretions sit in airways causing infection, and inflammation, causing lung damage
  • Also impairs HCO3 transport, decreasing GIT pH
  • and reduced hydration to other organs

Disease classification

Other issues due to reduced CFTR function

  • Reduced pancreas function, reducing fat absorption, thus reduced fat soluble vitamins and minerals absorption.
  • GIT pH changes, can cause absorption issues.
  • Excessive loss of NaCI in sweat, causing dehydration
  • Lung inflammation.

Class 1: No protein produced

Class 2: defective protein doesn't get to cell surface (F508del defect)

Class 3: Gating mutation - CFTR gets to surface but Cl doesn't flow.

Class 4: Poor flow rate by the CFTR

Class 5: Functional CFTR but not enough on the surface

Class 6: Protein functional but unstable (F508 del defect)

Diagnosis

  • Sweat test - CL > 60mmol/L = confirmed CF (NR 10-20)
  • New born screening - Immuno Reactive Trypsin as part of the Guthrie test.

Population screening?? - Cost, ethical and religious issues

  • if CF postive, what would you do to the fetus? - very unethical

Historically - failure to thrive, chronic respiratory infections and underweight. Meconium ileus (GIT obstruction) at birth, male infertility, pancreatitis, liver disease.

Child: Coughing, hot, ill and distressed - potential CF?

If diagnosed: there is severe pill and medication burden and very costly.

Goals of therapy

2 main areas: lung and GI disease.

  • Maintain lung function and reduce the frequency of exacerbations. If more exacerbations occur, more problems will occur down the track
  • Give and maintain adequate nutrition to maintain the lung function. Low BMI is a predictor of mortality and high BMI is associated with better lung function.

Treatment stratgies

Bacteria in children: Haemophilus and Staphyloccous
Later in life: Pseudomonas Aeruginosa in almost all pateints.

  • PA Non-mucoid: essentially no biofilm yet thus can be treated effectively. Recommended to treat aggressively to prevent Mucoid stage.
  • PA Mucoid: Very difficult to treat and drugs have reduced effectiveness

Aggressive treatment of lung disease

  • Specialised CF clinic
  • Optismising lung function + Physiotherapy
  • Optimise nutrition
  • Aggressive antibiotics (oral or inhaled, IV if required)
  • Review and monitor

We can clear the intial infection but eventually regrows and and cycle continues, constantly damaging lung function

Pseudomonas Colonisation: poorer PFTs and prognosis

  • Can be delyaed with first growth treatment but eventually colonised and unlikely to eradicate.
  • Detection of growth via broncoscopy or given saline to cough and discharge is sent for culture.
  • Eradication protocols are different based on hospital with > 80% success rate but regrows in 1-2 years.

Symptoms

Increased sputum, coughing, weight loss, fall in PFTs

Acute treatment

May initially try oral Ciprofloxiacin + inhaled tobramycin (or colistin) for 2 weeks - to avoid hospital

2 anti-PAs IV + inhaled anti-PA with intensive physiotherapy to push mucous out, at hospital or home, major advantage in hosp. is physio therapy

Generally 2 antibiotics given with 2 different MOA to prevent resistance

Effects of CF + Treatment

IV drip lines: not recommended as patient requires many doses of IV infusion and multiple catheter lines can weaken veins

  • PICC - into larger vessels = less irriation and last for 2 weeks
  • PORT-A-CATH = implantable port that can last for years

Tobramycin

TDM measured by peaks and troughs for Cmax and AUC after 1-2 hours administering dose.
Gives a clearer picture as troughs can be lower but AUC can be high = more exposure.

  • Results can available before second dose and can detect early changes in renal function which is missed with pre-dosing technique.

Pre-dosing = measuring concentration before next dose. If concentration too high toxicity occurs

2 samples used for first TDM then 1 sample at either 1 hour or between 4-6 hours after infusion to gather data

Potential errors

Administration errors: dose, infusion time, dosing time, all doses given?

Sampling: too early?

If numbers don't make sense or doesn't follow historical trend, repeat it later and check again.

Side effects

Nephrotoxicity: more courses of tobramycin, the greater risk of permanent kidney damage.

  • Measuring GFR: invasive and expensive but very good and sensitive.
  • Calculating GFR: simple and easy, but depends on msucle mass and patients are generally less muscle and no change in SeCr until 50% kidney function is loss.
  • Renal biomarkers: Cystatin C, Osteopontin, etc

Oto-toxicity: irreversible damage to inner ear hair cells.

  • Vestibular toxicity: ataxia and nystagmus - maybe permanent
  • Cochlear toxicity: high frequency hearing loss - then severe loss of general hearing.

Monitoring is variable as hear declines with age and as humans we cannot hear higher frequencies.

Non-tuberculous Mycobacteria

  • Increasing incidence and difficult to treat
  • Increasing morbidity and mortality with decline in lung function
  • Treated with long term therapy of highly toxic agents

Sputum removal

  • Chest physiotherapy and exercise (main stay and should always be used monotherapy or in combo)
  • Recombinant DNAse inhalation = splits DNA and proteins making the mucous more runny
  • Hypertonic saline 3-6% = drives water into surface but makes you cough (pre-treated with salbutamol to open airways and reduce irritation)
  • Mannitol inhalation = drives water in but makes people cough

Nebulisers

Slow and takes time (20mins daily per dose), used with dry powder inhalations

eFlow: Vibrating mesh nebuliser whihc delivers medicine in 7mins/dose

Anti-inflammatories

Gastro-intestinal Disease in CF

Good nutrition = Good lung function
Creon: pancreatic enzyme replacement therapy.

  • Capsules with EC granules
  • Adjust dose based on bowel action
  • Dose depends on diet and extent of pancreatic dysfunction

Poor Nutrition = Poor lung function
Lack of pancreatic enzymes = poor digestion of fats and foods, causing a lack of nutrition and poor absorption of fat soluble vitamins.
Dietitian is important for proper nutrition in these patients

To break the cycle of infection - inflammation - infection.

  • Oral prednisolone: not given long term.
  • ICS: not routinely used unless patient has asthma.
  • NSAIDs (ibuprofen): inhibits neutrophils migration but at high dose and TDM required. Moinitor side effects.
  • Macrolides (Azithromycin): anti-infective and immunomodulating properties increases muco-ciliary CL and prevents biofilms. Given 250-500mg TDS but monitor S/E (ototoxic, QT interval and staph resistance).

Bone Health

Osteoporosis and Osteopenia is common in CF.
Risk Factors:

  • Malabsorption
  • Diabetes
  • Inflammation
  • Vitamin K and D deficiency
  • Lack of CFTR in the bones

Managed with proper nutrition, vitamin K, D and Ca2+ supplement and exercise.

  • Bisphosponates can cause more bone pain in CF and may cause GORD in CF patients
  • Try IV Denosumab or Zoledronic acid?

CF Liver Disease

Major cause of morbidity and shortened survival

  • No CFTR = Decreased biliary secretion
  • Bile becomes viscous and obstruction occurs retaining toxic bile acids

Treatment: Ursodeoxycholic acid and natural bile acids

  • Not PBS for CF (Only for primary liver disease)
  • Replaces cytotoxic acids, stimulates flow and reduces viscosity.
    Other treatment - Liver transplant (if too damaged)

CF Diabetes

Different from Type 1 and 2
Associated with reduced insulin and increased insulin resistance.
Treatment: Insulin (Other agents appear to be ineffective) + Lifestyle modification

Changes to body PK

Oral Absorption:

  • Reduced bile acid secretion
  • GI motility
  • Pancreatic function
  • HCO3: less EC breakdown

Distribution:

  • Changes to Vd
  • Reduced plasma proteinn binding
  • Lower lean body and fat mass

Clearance:

  • Increased GFR and tubular secretions/reabsorption
  • lower lean body mass and fat free mass = changes to clearance

New medicines and Formulations

Tobi-Inhaler Solution: 300mg/5mL given BD with monthly on/off alternating with colistin inhaled.

  • Good increase in FEV1 and reduce exacerbations and mortality.
  • Side effects: well tolerated, cough and brochospasm first dose.

Tobramycin Inhaled powder: phospholipid particles = lower dose

  • Equally effective
  • Ivacaftor: potentiator of CFTR and 3A4 Substrate
  • Increases CFTR activity on surface by opening the gate, very effective in normalising sweat chloride biomarker
  • Side effects: increased CI and HCO3 secretions
    • increase BMI/Fat and lean mass
    • normalised GI biome
    • increased fat absorption
  • Thus caution is overweight and obesity
  • Other side effects: Ab pain, diarrhoea, dizziness and UTIs risk
    • Hepatotoxicity: monitor LFTs and ALT etc
    • Cataracts: esp in children thus monitor

Orkambi: Combination of ivacaftor and lumacaftor

  • Lumacaftor: a corrector, increases the number of CTFR on surface.
    • Minor increase in FEV1 but reduces hospitalisations and exacerbations, maintaining FEV1
    • Lumacaftor itself is a 3A4 inducer thus higher doses of ivacaftor is required. Also reduced OCP.
  • Concerns: Acute SOB and fall in FEV1 on first dose - drives non-adherence. High potential for DDIs and false positive for cannabis

Symdeko: Tezacaftor and Ivacaftor

  • Tezacaftor daily dosing and not a CYP inducer but a CYP enzyme substrate.
  • Very good options and well tolerated.

Trikafta: triple therapy with 2 correctors and 1 potentiator

  • Elexacaftor + Tezacaftor + Ivacaftor
    • very effective and can treat dual F508del mutations
  • Major change in QoL = can exercise

Role of Pharmacists

  • Provide education and counselling
  • Drug-dose advice: altered PK and polypharmacy
  • Family and patient advice + support
  • Adherence and monitoring/HMRs

Colistmethate Sodium (Colistin):

  • Fantastic anti-PA and difficult to develop resistance
  • Very potent but does have renal toxicities
  • Not used as monotherapy

Anti-PAs = Ciprofloxacin, Tobramycin, Colistin

Azithromycin: