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Respiratory Drugs > Pharmacotherapy Of Cystic Fibrosis > Flashcards

Pharmacotherapy Of Cystic Fibrosis Flashcards

1
Q

What is the aim of the therapy of CF?

A

Improve CFTR function and expression at the cell surface, help keep a balance of salt and water in certain organs like the lungs

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2
Q

What are the examples of potentiators?

A

Ivacaftor and Elexacaftor

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3
Q

Which classes do the potentiators target?

A

Gating mutation (Class 3)
Conduction mutations (Class 4)
Insufficient protein mutations (Class 5)

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4
Q

What is gating mutation (class 3)?

A

CFTR forms a channel that does not open properly

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5
Q

What is a conduction mutation (class 4) ?

A

Malformed channel is produced, which limits the rate of chloride and bicarbonate movement

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6
Q

What is an insufficient protein mutation (class 5)?

A

The amount of CFTR protein present at cell surface is not sufficient. This can be caused due to too little production or increased rate of channel removal

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7
Q

Mechanism of action of potentiators?

A

Help open the CFTR channel and increase the flux of chloride and bicarbonate across the cell surface

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8
Q

What are the examples of correctors?

A

Elexacaftor, Lumacaftor, Tezacaftor

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9
Q

Which classes do correctors target?

A

Processing mutation (Class 2)

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10
Q

What is a processing mutation?

A

CFTR protein is created but misfiles, preventing it from reaching the cell surface

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11
Q

What is the mechanism of action of correctors?

A

Help normalise the folding of defective CFTR protein and its movement to the cell surface

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12
Q

Which classes do amplifiers target?

A

Process, gating, condition and insufficient protein mutation (Classes 2 to 5) –> A channel is created with limited activity

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13
Q

What is the mechanism of action of amplifiers?

A

Increase production of the CFTR protein

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14
Q

Which classes do stabilisers target?

A

Process, gating, condition and insufficient protein mutation (Classes 2 to 5) –> A channel is created with limited activity

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15
Q

What is the mechanism of action of stabilisers?

A

Limit removal and degradation of CFTR protein from the cell surface

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16
Q

Which kinds of modulators are not approved for clinical use yet?

A

Amplifiers and stabilisers

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17
Q

What is an example of production-correctors?

A

Ataluren

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18
Q

Which classes do production-correctors target?

A

Class 1 CFTR mutation (protein synthesis defect)

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19
Q

Mechanism of action of production-correctors?

A

Promote the read-through of premature termination codons in mRNA, generating more production of CFTR protein.

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20
Q

What happened to Ataluren?

A

Production was terminated due to lack of efficacy in phase 3 trials

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21
Q

What is the recommended treatment for CF patients who are ≥2 years old?

A

Elexacaftor-Tezacaftor-Ivacaftor (ETI)
(corrector/potentiator - corrector - potentiator)

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22
Q

When is ivacaftor mono therapy suggested?

A

Patients as young as one month with responsive mutations

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23
Q

When is lumacaftor - ivacaftor treatment given?

A

For patients 1 to 2 years of age

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24
Q

What is the suggested sequence of treatment for a patient who is eligible for multiple kinds of therapies due to their mutations?

A

ETI > dual therapy > mono therapy

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25
Q

When is tezacaftor-ivacaftor treatment recommended?

A

Patients ≥ 6 years of age when ETI is not available or with approved mutations

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26
Q

Which kind of mutation was Ivacaftor designed to treat?

A

G551D mutation (gating mutation) in at least one of GFTR genes

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27
Q

Mechanism of action of Ivacaftor?

A

Binds to defective CFTR protein and increases the probability of the open conformation of the mutant chloride channel.
Increased chloride and bicarbonate ion transport

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28
Q

What are the side effects of Ivacaftor?

A

Headache, nasopharyngeal pain & URTI

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29
Q

In dual combination therapy, which two kinds of drugs are mixed?

A

The potentiator is mixed with a corrector to improve CFTR function

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30
Q

What are the side effects of dual therapy?

A

Overall well tolerated –> good safety profile.
HOWEVER, chest discomfort and dyspnea might appear due to lumacaftor

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31
Q

Pharmacokinetics of all CFTR modulator treatments?

A

Oral
Dosing depends on age and weight
Should be taking with fat-containing foods
Hepatic impairment –> dose reduction
Drugs that inhibit CYP3A4 –> dose reduction

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32
Q

Which foods should be avoided with the CFTR modulators therapy?

A

Foods that contain grapefruit

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33
Q

What are the side effects of triple therapy?

A

Well tolerated
Abdominal pain, diarrhoea and rash

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34
Q

What kind of tests need to be done to the patients prior to CFTR modulator treatment is initiated?

A

Measurement of liver transaminases (ALT & AST) and serum bilirubin, with ongoing monitoring every three months for the first year and then annually.

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35
Q

When should ETI be interrupted?

A

If ALT or AST are more than x5 normal
OR
ALT or AST are x3 normal AND bilirubin x2 the upper limit

36
Q

Why does a reduction in CFTR function/expression cause multi-system disease?

A

CFTR proteins are expressed in the epithelial cells of many different organs

37
Q

IN the CF lung what does a shift in electrolytes cause?

A

Increase in water absorption –> thickened/viscous mucus
Accumulation of mucous –> recurrent infections and inflammation

38
Q

What are the most common causes of morbidity and mortality for CF patients?

A

Decline in pulmonary function and pulmonary failure

39
Q

What are the therapeutic objectives of CF therapy?

A

Correction of the Main Defect
Reduction in Mucus Burden
Control of Infection
Control of Inflammation

40
Q

Who is eligible for targeted therapy?

A

Patients < 12
Patients ≥ 12 who are on ETI and have moderate to severe lung disease
Patients ≥ 12 who are not on ETI

41
Q

What are the airway clearance therapies?

A

Coughing and huffing / chest physical therapy –> techniques that loosen sticky mucus so it can be cleared

42
Q

Which other therapies can be use for reduction of mucus burden?

A

Bronchodilators
Mucolytics
Inhaled / oral antibiotics

43
Q

Which kind of bronchodilator should be used in the treatment of CF?

A

β2 agonists

44
Q

When should the bronchodilators be given?

A

Before starting airway clearance treatment

45
Q

What is the function of the bronchodilators?

A

Help to widen the airways by relaxing the muscles lining the airway wall

46
Q

Examples of bronchodilators (β2 agonists)?

A

Salbutamol, Albuterol

47
Q

When are mucolytics taken? How?

A

Can be taken during airway clearance therapy; nebulised

48
Q

What is the function of mucolytics?

A

Help to thin and then move the mucus out of the airways so it can be coughed out.

49
Q

What are the different kinds of mucolytics?

A

Inhaled Dornase alfa (Dnase)
Inhaled hypertonic Saline
Inhaled mannitol

50
Q

What is Inhaled Dornase alfa?

A

It is an endonuclease that cleaves and depolymerizes extracellular long-chain DNA in the sputum –> reducing mucous viscosity and preventing airway infection

51
Q

What is the pharmacokinetics of Inhaled Dornase alfa?

A

Once daily via inhalation

52
Q

What is the mechanism of action of inhaled hypertonic saline?

A

The high osmolarity of the solution induces an osmotic flow of water into the mucus layer –> rehydration of airway surface liquid and improving mucociliary clearance

53
Q

How would you improve efficacy of mucolytics?

A

Combination of hypertonic saline with Dnase

54
Q

Pharmacokinetics of Inhaled hypertonic saline?

A

Given twice daily

55
Q

What is inhaled mannitol?

A

A sugar alcohol that is used as an osmotic agent.

56
Q

What happens when inhaled mannitol is inhaled?

A

It creates an osmotic gradient that facilitates water flow into lumen of airway –> increasing the volume of airway surface liquid and improving clearance of mucus

57
Q

When is inhaled mannitol used?

A

Second-line option to replace Dnase/hypertonic saline combination

58
Q

What is a contraindication when it comes to inhaled mucolytics?

A

Inhaled medications should not be mixed together in the same nebulizer

59
Q

Why are inhaled antibiotics given to CF patients?

A

They develop chronic bacterial infection within the airway

60
Q

When should the antibiotics be taken?

A

After the airway clearance therapies as the lungs are clear of mucus allowing the medication to reach deeply into smaller areas to attack bacteria

61
Q

Which medication should be given if P. aerugonisa is detected?

A

Inhaled tobramycin should be given for 28 days

62
Q

What are the other alternatives to inhaled tobramycin?

A

Inhaled aztreonam
Inhaled colistin

63
Q

When is tobramycin prescribed and why?

A

Prescribed for treatment of both superficial and deep infections because of the broad spectrum

64
Q

What is the mechanism of action of tobramycin?

A

Inhibits protein synthesis: Aminoglycosides bind to 30s subunits and interfere with three different ways

  1. Block formation of the initiation complex
  2. Cause misreading of the code on mRNA template
  3. Inhibit translocation
65
Q

What are the pharmacokinetics of tobramycin\?

A

Half-life of about 2 hours
Metabolised in the liver (minimally)
Excreted via the kidneys
Low therapeutic index

66
Q

What are the side effects of tobramycin?

A

GI disturbances, headache, skin rash.
Can induce ototoxicity, neuropathy and nephrotoxicity

67
Q

What is an example of a β - lactic antibiotic?

A

Aztreonam

68
Q

When is aztreonam used?

A

To treat infections caused by gram-negative bacteria

69
Q

What is the mechanism of action of aztreonam?

A

Inhibits synthesis of the bacterial wall by blocking peptidoglycan crosslinking –> bacterial death

70
Q

What are the side effects of aztreonam?

A

Wheezing, coughing and vomiting

71
Q

What is aztreonam often used as alternative to and why?

A

Alternative to aminoglycosides because it is not ototoxic or nephrotoxic

72
Q

What is an example of a polymyxin antibiotic?

A

Colistin

73
Q

How does colistin work?

A

It binds to lipopolysaccharides and phospholipids in the outer cell membrane of Gram-negative bacteria.

74
Q

Mechanism of action of colistn?

A

Displaces divalent cations from the phosphate groups of membrane lipids, which leads to disruption of the outer cell membrane –> leakage of intracellular contents –> bacterial death

75
Q

Pharmacokinetics of colistin?

A

There is no GI absorption
It can be given inhaled or parentrally

76
Q

What are the side effects of colistin?

A

Nephrotoxicity and neurotoxicity

77
Q

What is an example of oral antibiotic?

A

Azithromycin

78
Q

What is azithromycin?

A

It is a macrolide antibitic that has been shown to benefit those with chronic P. aeruginosa infection

79
Q

Why is azithromycin given to patients even though they are usually resistant?

A

The benefits are due to its anti-inflammatory effect

80
Q

What is a dominant pathologic feature of the airways of CF patients?

A

Neutrophilic inflammation

81
Q

What is an example of NSAIDs that is used in CF patients?

A

Ibuprofen

82
Q

Who is Ibuprofen usually given to ?

A

High-dose oral ibuprofen is usually given to children and young adolescents with good lung function

83
Q

What is the main role of Ibuprofen?

A

Agent to reduce airway inflammation

84
Q

When are ICS given in patients with CF?

A

When they have symptoms of asthma

85
Q

When is lung transplantation an option?

A

When all other medical treatments have failed

86
Q

What is a major Gi contributor to malnutrition of CF patients?

A

Pancreatic dysfunction

87
Q

What are the pharmacologic options to be given to Cf patients struggling with malnutrition?

A

Growth hormone
Appetite stimulants
Insulin

Respiratory Drugs (4 decks)

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