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Respiratory Pharmacology > L11 - genetic determinants of lung function/personalised medicine > Flashcards

L11 - genetic determinants of lung function/personalised medicine Flashcards

1
Q

CF genetics

A

autosomal recessive

defect in long arm of chromosome 7 coding for CFTR protein

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2
Q

CFTR mutations

A

over 1600 mutations

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3
Q

F508del mutation

A

causes CFTR 44% homozygous

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4
Q

CF carrier ratio

A

1:25

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5
Q

CF birth ratio

A

1:25,000

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6
Q

CFTR protein

A

transport protein on membrane of epithelial cells for chloride and thiocyanate ions

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7
Q

Normal CFTR protein

A

moves chloride ions to the outside of the cell

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8
Q

Mutant CFTR protein

A

does not move chloride ions, causing sticky mucus to build up on the outside of the cell

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9
Q

Abnormal CFTR protein leads to…

A

Dysregulated epithelial fluid transport, leading to thickened secretions in a number of organs

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10
Q

% in lung and GI involvement

A

80%

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11
Q

% in lung alone

A

15

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12
Q

Failure of mucocilliary clearance leads to…

A

with impaired immune function this contributes to continued insult to the bronchial wall, through the recruitment of inflammatory cells and uncontrolled neutrophilic inflammation

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13
Q

Pathophysiology flow chart

A
  1. Microbial insults
  2. Defect in host defence
  3. Respiratory tract infection
  4. bronchial inflammation
  5. Respiratory tract damage
  6. progressive lung disease
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14
Q

Bronchitis leads to

A

Bronchiectasis resulting in fibrosis

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15
Q

Clinical symptoms

A

Frequent infections, malabsorption, failure to thrive

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16
Q

Abnormal salt/chloride exchange

A

raised skin salt and impaired nasal potential difference

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17
Q

% diagnosed by 6 months

A

50%

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18
Q

% diagnosed by 8 years

A

90%

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19
Q

Normal symptoms

A

fatigue, chronic cough, recurrent URIs, thick mucus, chronic hypoxia, decreased absorption of vitamins and enzymes, abdominal distention, decreased digestive enzymes, rectal prolapse, meconium ileum in newborns

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20
Q

Treatments

A

increased calories and protein, chest physiotherapy, breathing exercises and aerosol therapy

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21
Q

Medications

A

antibiotics, supplement vitamins, aerosol bronchodilators, mucolytics and pancreatic enzymes

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22
Q

Bromchiectasis

A

90% surviving neonatal period

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23
Q

Infertility in males

A

98%

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24
Q

Infertility n females

A

20%

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25
Q

Pancreatic insufficency

A

malabsorption 85%

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26
Q

CF-related diabetes

A

50% by age 30

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27
Q

CF chronic liver disease

A

25%

28
Q

Cirrhosis

A

10%

29
Q

Sinonasal polyps

A

10-25%

30
Q

Distal intestinal obstruction syndromex

A

20%

31
Q

Arthropathy

A

10% adults

32
Q

Meconium ileus

A

10-20% in infants

33
Q

Low bone mineral density

A

10-25%

34
Q

Pneumothorax

A

4-20%

35
Q

Allergic lung disease

A

7%

36
Q

Rescue antibiotics

A

2 week course
access is central/peripheral
home vs. hospital
issued with frequent antibiotics = allergies, renal impairment, resistance and access problems

37
Q

CF prevention management

A

segregation, surveillance, eradication infections early, antibiotics, airway clearance physiotherapy, bronchodilator and exercise, psychosocial sport, vaccinations, potentially lung transplant

38
Q

Nutrition prevention

A

pancreatic enzymes, diet high calories and fat, supplements including vitamins, percutaneous feeding

39
Q

Personalised medicine

A

individual tailored medicine, stratified based on predicted response or risk of disease, genetic information major factor

40
Q

Personalised medicine advantages

A

increased adherence to treatment, improved quality of life, prolongs life, help avoid adverse drug reactions/intolerances, shift the emphasis in medicine from rescue to prevention, help control overall healthcare costs, direct selection of optimal therapy and reduce trial-and-error prescribing, reveal additional or alternative uses for medicines and drug candidates

41
Q

Personalised medicine in CF

A

useful as it is a monogenic disorder, less known influence of environmental factors
Well characterised pathophysiology with clear therapeutic targets

42
Q

Genotype-directed therapies

A

CF monogenic recessive diroder, malformed chloride pump leads to multi system disorder, different classes of defect

43
Q

Class 1

A

not synthesised
Nonsense frameshift or splicing mutations
prevents biosynthesis

44
Q

G542X

A

no synthesis

45
Q

Class 2

A

Reduced trafficking, misfiling in the ER< leading to an absence of functional protein at the cell membrane

46
Q

F508del

A

Reduced trafficking with ER misfolding

47
Q

Class 3

A

reduced gating, CFTR protein reaches membrane but less opening

48
Q

G551D

A

reduced gating

49
Q

Class 4

A

decreased conductance, protein reaches cell membrane but abnormal conformation of the pore leading to disrupted ion flow

50
Q

R117M

A

decreased conductance

51
Q

Class 5

A

Reduced synthesis so less protein at the cell membrane

52
Q

A455E

A

reduced synthesis

53
Q

Ivacaftor

A 
CFTR potentiator for class II mutations, i.e. G551D
improves FEV1, MI and QoL
54
Q

Potentiator

A

potentiates chloride secretion via increasing the CFTR channel opening time

55
Q

Orkambi

A 
Combined Ivacaftor and Lumacaftor
Potentiator and corrector
improves stabilisation and processing so more on cell surface
Class II mutations
only available on compassionate use
56
Q

orkambi side effects

A

bronchospasm, GI upset and rash

57
Q

CFTR correctors

A

corrects cellular misprocessing of CFTR to facilitate transport from the ER
improves stabilisation and processing to increase presence on cell surface

58
Q

Symkevi/Symdeko

A 
Combined Ivacaftor and Tezacaftor
Corrector and potentiator
Class II mutations
compassionate use programme
less side effects
59
Q

Tripe therapy

A

VX445 and Symkevi
Corrector and potentiator
new drug
final results not known

60
Q

Other agents under review

A

gene therapy, inhaled therapies and intravenous antibiotic therapies

61
Q

Challenges treating CF

A

adherence to treatment, high treatment burden, high cost, allergies/intolerances, different infectious organisms and drug resistance, restrictions, prevention vs. rescue

62
Q

Rescue treatment

A

disadvantages in terms of cost, time, decline in quality of life and life expectancy
side effects of recurrent intravenous antibiotic therapy

63
Q

Treatment burden

A

physiotherapy, nebulisers, exercise, oral medications, oral supplements, percutaneous nutrition, insulin, intravenous antibiotics

64
Q

Treatment burden time

A

all adds up to 2-4 hours treatment daily

65
Q

Adherence to medication

A

amongst people with long-term conditions estimated at 30-50%

66
Q

CF adherence to nebulisers

A

36%

Respiratory Pharmacology (17 decks)

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