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Drug Treatment of Disease > Respiratory Disease (1) Cystic Fibrosis > Flashcards

Respiratory Disease (1) Cystic Fibrosis Flashcards

- Be able to describe the pathophysiologies associated with CF - Outline the main genetic cause of the disease in the context of treatment - Current main approaches for the treatment including the main drug classes and their rationale for use - Discuss impediments to new therapeutics and future directions

1
Q

Pathophysiology Overview

A
  • Ion conductance abnormalities
- Thick sticky mucus
>Malnutrition
>Frequent respiratory infections
>Breathing difficulties
>Permanent lung damage

(In healthy lungs, mucus forms gel-like protective barrier)

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2
Q

Pathophysiology (GIT)

A
  • Pancreatic insufficiency
  • Gastrointestinal symptoms
    >Frequent diarrhoea
    >Bulky or foul smelling stools
    >Excessive appetite, but poor weight gain
    >Meconium ileum (obstruction of bowel at birth)
    >Distal intestinal obstruction syndrome
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3
Q

Pathophysiology (Respiratory)

A
  • Compromised mucocilary clearance
  • Lung inflammation
  • Lung infection
    >Haemophilus influenza
    >Staphylococcus aureus
    >Pseudomonas aeruginosa
  • Induction of cytokines
  • Amplifying cycle of infection, inflammation & mucus secretion

> > > > Bronchiectasis
Pulmonary insufficiency
Death

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4
Q

Colonisation with pathogens impairs lung function

A
  • Percent Predicted FEV1 drops to 60% by 18-24yrs, stays around that level till 45+
  • S. aureus and H. Influenzae common in childhood, but infection rates drop over time
  • P. Aeruginosa Low infection rates in childhood, but rise significantly over time to 80% by adulthood (18-24yrs)
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5
Q

Vicious cycle of chronic airway inflammation

A

1) P. Aeruginosa products cause neutrophil death
>when apoptotic cells not rapidly cleared
>necrosis ensues

2) Proteases are released
>cause inflammation and
>tissue damage
>also cleaves (3)

3) CXCR1 (chemokine receptor) from the surface of any viable neutrophils

4)This cleavage reduces neutrophil killing of P. Aeruginosa by
>impairing neutrophil responses to IL-8

4)b) At the same time, the cleaved fragments activate TLR2 on epithelial cells
>more inflammation and neutrophil recruitment

5) Result in
>dysregulated chronic inflammatory response
>bacterium is able to persist

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6
Q

Pathophysiology (other)

A 
>salty sweat (excessive loss of salt)
>chronic rinosinusitis
>fungal infections with aspergillus
>reflux
>rectal prolapse
>Male infertility (abnormal/absent vans deferens)
>Liver disease
>Osteoporosis
>CF diabetes
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7
Q

Genetics

Mendelian Inheritance

A

Autosomal recessive trait

> child born of two CF carriers 25% likelihood of being afflicted with CF
gene causing cf carried by about 3% of Caucasian population

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8
Q

CFTR gene

A

Gene codes for membrane associated protein known as CFTR

>caused by large single gene located on Chr7 which is known as CFTR

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9
Q

CFTR protein

A 
Cl- Ion channel through cellular membrane
>extracellular carbohydrate side chains
>transmembrane regions
>2 ATP binding sites
>1 regulatory domain
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10
Q

CFTR gene mutations

A

Spectrum of mutations that affect its function
>1 in 28 Caucasians carry the most frequently encountered defective gene mutation
>Deletion of phenylalanine at position 508
>ΔF508-CFTR

> > This mutation responsible for about 70% cases worldwide

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11
Q

CFTR Mutation Classes

A

More than 2000 CFTR mutations identified
>categorised in functional classes 1-6

Classes 1-3
>non-functional CFTR protein
>pancreatic insufficiency

Classes 4-6
>some CFTR function
>pancreatic sufficiency

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12
Q

CFTR Class 2 Mutation

A

> Defective trafficking of CFTR to incorrect location
or presentation of non-functional CFTR

> ΔF508 by far most common
70% prevalence
50% homozygous
>major target for CF therapy

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13
Q

CFTR Class 3 Mutation

A

> Defective regulation of the channel opening
G551D mutation
>CFTR protein that is localised on epithelial membrane but fails to open
4% of CF patients

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14
Q

Epidemiology

A
  • 80,000 PTs worldwide
- Prevalence
>Europe: 7.4 per 100,000 population
>North America: 1 in 3400 births
>Australia: 1 in 2500 births
>Japan: 1 in 350,000
>India: 1 in 40,000

CF predominantly occurs in white people of Northern European descent

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15
Q

Morbidity and Mortality

A

Once: always fatal
1960s: Median survival <5 years
Mid 1960s: first comprehensive treatment strategy
Today: Life expectancy ~35-39 years

Impact of research on survival
>Pancreatic enzymes
>airway clearance
>antistaphylococcal antibiotics
>antipseufomonal antibiotics
>lung transplant
>DNase
>Inhaled Tobramycin
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16
Q

2014: Update on most recent mortality data

A

Life expectancy of male patients consistently longer than women
>gender gap persists to date

Socioeconomic status, race, ethnicity, ambient air pollution
>found to have significant impact

Access to health insurance is another determinant of survival
>especially a problem in the US

Eventually, 75% succumb to chronic progressive lung disease

17
Q

Cost of healthcare

A

Prescription drugs, outpatient visits, durable medical equipment
>US$29,718/PT/year (2007)

Since 2015
>CFTR Modulators
>US$250k-300k/PT/Year

18
Q

Diagnosis

A

Sweat Test
>Measures levels of sodium and chloride in sweat collected on skin
>Repeated chloride values ≥60mmol/L and sodium values ≥70mmol/L are confirmatory

Chest x-rays, lung function test (FEV1), sputum cultures, stool evaluations confirm the diagnosis

19
Q

Screening

A

Recommended:
>prenatal or preconception carrier screening
>only screens 23 most common mutations

Broad screening kits (up to 97 mutations)
>CFplus
>Tag-It Cystic Fibrosis Kit
>xTAG Cystic Fibrosis 39 Kit v2
>VariantPlex CFTR Kit
20
Q

Prevention

A

At present, as a disease with a genetic basis, CF cannot be prevented

Until gene therapy to treat the underlying cause becomes available, disease incidence can only be decreased through genetic testing and counselling of prospective parents found to be at risk of transmitting two copies of CFTR

21
Q

Treatment

A

Depending on stage of disease and organs involved

Daily baseline therapy:
>improve mucus clearance
>decrease inflammation
>control infection
>CFTR protein modulation

> > More aggressive therapy during acute exacerbation
End stage: Lung transplant

22
Q

Drugs:

Antibiotics

A 
Ciprofloxacin hydrochloride (Cipro)
Meropenem (Meronem)
Tobramycin (TOBI)
Colistin sulphae (Promixin)

Aztreonam L-Lysine (cayston)
Levofloxacin (Quinsair)

23
Q

Drugs:

Drugs improving mucociliary clearance

A 
Dornase alpha (Pulmozyme)
Mannitol (Bronchitol)
24
Q

Drugs:

Agents improving CFTR protein function

A

Ivacaftor (Kalydeco)
Ivacaftor/Lumacaftor (Orkambi)
Ivacaftor/Tezacaftor (Symdeco)

25
Q

Drugs:

Agents for pancreatic insufficiency

A

Pancrelipase (Creon, Zenpep, Pancreaze)

26
Q

Antibacterial Agents

Why do we use them?

A

Defective/Deficient CFTR
>Thick sticky mucus buildup in respiratory tracts of CF PTs
»Ideal breeding ground for microorganisms

Microorganisms most problematic to CF PTs are virtually innocuous in healthy individuals
>P. aeruginosa most common
>Gram-negative, nonmotile bacterium
>identified in sputum of 80% of all CF patients in mid 20s
>near impossible to eradicate

Downwards spiral of lung infection
>First infection
>Inflammation
>Recurrent infection
>Chronic infection

Antibiotic treatment is dependent on severity of infection and isolate

27
Q

Antibiotics:

Ciprofloxacin

(and meropenem: beta-lactatam antibiotic)

A
  • Quinolone antibiotic
  • Oral form
  • Used in mild illness
-MOA:
>inhibit DNA gyrase
>inhibit a type II topoisomerase
(Topoisomerase IV)
>>necessary to separate bacterial DNA, thereby inhibiting cell division
  • effectively substitutes one course of IV antibiotics in PTs with mild disease caused by susceptible organisms
  • May be taken w/wo food as directed by doctor, usually twice a day (every 12 hours)
- Side effects
>nausea
>diarrhoea
>dizziness
>lightheadedness
>headache may occur
28
Q

Antibiotics:

Tobramycin inhalation solution (TOBI)

A
  • Inhaled aminoglycoside antibiotic for CF
  • TOBI combats P. Aeruginosa in CF

> administered twice daily for 28-day course
effective and well tolerated therapy for early P.aeruginosa infection in PTs with CF
associated with important therapeutic gains in adolescents with CF who normally lose lung function more rapidly than in any other age group

  • MOA:
    >binds to site on bacterial 30S and 50S ribosome
    >prevent formation of 70S complex
    >mRNA cannot be translated to protein
    >Cell death
    >also binds to RNA-aptamers
    (Artificially created molecules to bind to certain targets)
29
Q

Antibiotics:

Levofloxacin

A
  • First fluoroquinolone as inhaled therapy
    (Oral levofloxacin used for e.g. skin infections but in CF used as inhalation)
  • Indicated for management of chronic infections with P. Aeruginosa in adult CF patients
  • Extensive renal elimination
  • Enhanced penetration into lungs and P.aeruginosa biofilms (high concentrations in sputum and Low serum concentrations)
  • Comparison: inhaled antibiotic (trobramycin) in 282 participants, showed levofloxacin inhaled was at least as good as Tobramycin at improving FEV1 after 1-3 treatment cycles

Rationale:
- lower respiratory tract infection with PA is associated with increased morbidity in PTs with CF

Objectives:
- this study assessed the efficacy and safety of a novel aerosol formulation of levofloxacin in heavily treated CF population with PA infection

Nebulised Levofloxacin was well tolerated and demonstrated significant clinical efficacy in heavily treated patients with CF with PA lung infection

30
Q

Agents improving mucociliary clearance

DNase alpha Inhalation

A
  • Recombinant human DNase or dornase alpha (Pulmozyme)
  • Inhaled
  • Helps thin the mucus in the lungs
    >coughed out more easily
  • Most of the DNA is of host origin

MCC removes foreign material from lung (defence mechanism)
>CF abnormal or insufficient airway clearance

Neutrophils play dual role in CF
>both anti inflammatory and pro inflammatory effects
>In response to bacteria in airways, neutrophils are recruited to lungs to fight infection
>WBCs die while fighting
>Subsequent decomposition releases their genetic material into mucus
>Sticky DNA aggravates the already excessive stickiness of mucus
>initiate vicious cycle of further airway obstruction, inflammation and infection

  • MOA:
    >recombinant form of human enzyme deoxyribonuclease I (rhDNase)
    >selectively cleaves DNA and cuts the Long DNA molecules
    >shorter, less sticky pieces
31
Q

Agents improving mucociliary clearance

Mannitol

A
  • Osmotic agent
    >increases osmolarity of periciliary fluid layer >water moves to lumen
    (Water from submucosa rehydrates airway surface liquid)
    >enhancing clearance of mucus
  • Delivery
    >dry powder inhalation
  • Improves mucus clearance and promotes effective coughing
  • Inhaled dry powder mannitol (Bronchitol)
    >add-on therapy to dornase alpha
    >or in patients intolerant of, or inadequately responseive to dornase alpha
32
Q

Agents improving CFTR protein function

Ivacaftor (Kalydeco)

A
  • First CFTR potentiator improving lung function
  • Potentiators: Increase cAMP-regulated aCl- ion channel open probability
    >increases Cl- secretion
    >reduces fluid absorption into airway epithelial cells
    >Increasing hydration of Airway Surface liquid
    >Resulting in increased ciliary beat frequency
  • Approved for gating mutation (Class III) G551D
    >in 2017 extended to include total of 33 mutations
33
Q

Agents improving CFTR protein function

Ivacaftor/Lumicaftor (Orkambi)

A

Orkambi
>indicated for CF PTs who are homozygous for F508del-CFTR
>Combination approved in 2015
>This mutation present in approximately one-half of U.S. CF population

Lumacaftor: Corrector
>facilitates processing and trafficking of CFTR to cell surface

> Improvement in lung function ppFEV1 (2.6 - 4 percentage points)
Reduction of pulmonary exacerbations (30-39% lower than placebo)

34
Q

Agents improving CFTR protein function

Ivacaftor/Tezacaftor (Symdeco)

A

Symdeco
>Indicated for CF PTs who are homozygous F508del-CFTR
>Combination approved in 2018

Tezacaftor: Corrector
>facilitates processing and trafficking of CFTR to cell surface

> > Two copies of F508del-CFTR
Or
one F508del and one mutation that results in residual CFTR function

35
Q

Agents for pancreatic insufficiency

A

PI occurs in > 85% of CF PTs

Enzyme preparation containing
>Pancrelipase
»Amylase, Protease, Lipase

> pH-sensitive, enteric-coated microspheres, microtablues or powders

36
Q

Supportive Therapy

A

Vitamin D
>Osteoperosis treatment

Physical therapy
>lung drainage, stimulate coughing, clear airway phlegm

Exercise

Lung transplant
>option for end stage pulmonary disease
>11% of lung transplants in U.S. are from CF patients
>40% of CF patients die while on waiting list
>Five year survival rate is 60%

37
Q

Drugs in Pipeline

A

Drugs to:

1) Restore CFTR function
(E.g. Ivacaftor, Orkambi, Symdeco)

2) Mucociliary Clearance
(E.g. Dornase alpha, Hypertonic saline)
>Inhaled mannitol (Bronchitol) only P3

3) Anti-inflammatory
(E..g Ibuprofen)

4) Anti-infective
(E.g. Amikacin Liposome Inhalation Suspension [Arikayce], Azithromycin)

5) Nutritional-GI-Other
(E..g AquADEKs, Pancrelipase Enzyme Products)

Drug Treatment of Disease (14 decks)

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