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Therapeutics > Session 2: Respiratory > Flashcards

Session 2: Respiratory Flashcards

1
Q

What are the three main pathways of the cough reflex?

A
  1. Sensory afferent pathways
  2. Central pathway
  3. Motor efferent pathway
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2
Q

Where does the sensory information travel to?

A

From the efferent pathway by the vagus nerve to the medulla oblongata

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3
Q

What happens when you cough?

A
  • Deep inspiration which increases thoracic pressure, the larynx is closed.
  • larynx opens and a high velocity jet of air ejects unwanted material out the mouth.
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4
Q

What are the different barriers that remove foreign objects?

A
  1. physical barrier: nasal hair, mucus, and epiglottis closes off the airways, cough and sneeze
  2. humoral barrier: local humoral factors (IgA, IgG)
  3. Cellular barriers: phagocytic cells (macrophages, neutrophils, dendritic cells)
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5
Q

Provide a brief overview of the cough reflex:

A
  • Irritants are sensed by the ‘cough receptors’ on the cell surface of nerves and epithelial cells.
  • These are ion channels stimulated by irritants
  • channel opens and cstions flood into the cell causing mebrane depoliaristion.
  • impulse is transmitted along afferent pathway via vagus nerve to the cough centre in th medulla.
  • cough centre generates efferent signal down nerve and vagus nerve to expiratory muscles.
  • triggers the cough reflec.
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6
Q

Up to how many weeks is considered as an acute cough?

A

3 weeks

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7
Q

How many weeks is considered as a chronic cough?

A

> 8 weeks

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8
Q

What is used to treat cough?

A

OTC cough meds and home remedies (honey and lemon)
- low dose of opioids (morphine) for chronic cough but can be addicting and has side effects such as constipation

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9
Q

What are TRPs?

A

Transient receptor potential cation channels

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10
Q

How is TRPV1 activated?

A

Hot temp >42 degrees
acid pH and capsaicin

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11
Q

Which TRPs are activated by cold temp and menthol?

A

TRPA1 and TRPM8

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12
Q

What is TRPV4 activated by?

A

Mechanical stretch and hypotonic solutions (cough when drowning)

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13
Q

How is ATP involved in the cough reflex?

A

ATP activates the purinergic receptors P2X3 on the nerve terminals which leads to calcium influx nerve depolarisation, generating an AP triggering a cough

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14
Q

What is the structure of cough receptor TRP

A

Family of 28 proteins characterised by 6 transmembrane spanning domains with N and C terminals. Pore-forming loop between helix 5 and 6. 4 of these subunits come together as homo or heterotrimers to form functional ions.

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15
Q

What are the features currently being investigated in the treatment of cough and why?

A

TRPA1 - is involved in the detection of oxidative stress which is seen in airway diseases
PGE2 - is elevated in chronic cough and can act on TRPA1 and TRPV1.
Proteases - released during damage seen in obstructive lung disease and act of TRPV4

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16
Q

What is the key diagnostic test for COPD?

A

Spirometry

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17
Q

What would a spirometer show in a COPD patient?

A

Airway obstruction (air cannot move out of the lungs as fast)
- Low FEV1 and FEV1/FVC ratio
- FEV1/FVC ratio less than 70%

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18
Q

What is the cause of airway obstruction in COPD?

A

Chronic bronchitis
Emphysema

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19
Q

What are chronic bronchitis and emphysema?

A

CB - inflammation and excess mucus due to hyperplasia of mucus secreting glands
E - alveolar membranes break down. Hyperinflation/ breath stacking

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20
Q

What is the main risk factor for COPD?

A

Smoking

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21
Q

What are the consequences of airflow obstruction in COPD?

A
  • Hyperinflation: dyspnoea threshold reached quicker.
  • Dynamic hyperinflation: tidal volume impaired during exercise, leading to air trapping
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22
Q

Name examples of short acting beta agonists?

A

salbutamol/ terbutaline

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23
Q

What are the indications of short acting B2 agonists (SABA)?

A
  • symptomatic relief and prevention of bronchospasm due to asthma, COPD, and airway obstruction conditions.
  • used prophylactically for exercise induced asthma
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24
Q

What is the MOA of SABAs/ B2 adrenergic receptor agonists?

A
  1. Drugs target beta-2-agonist receptors in SMCs.
  2. Stimulates adenylate cyclase enzymes.
  3. Drug binds and activates GPCRs
  4. G-protein stimulates adenlyse cyclase which increases cAMP production.
  5. Increasing protein kinase A (PKA)
  6. PKA inhibits phosphorylation of myosin
  7. Decrease in intracellular calcium = muscle relaxation.
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25
Q

What are the contraindications of SABAs?

A
  • In DM it can cause hyperglycaemia, it can also cause hypokalaemia when taken with diuretics such as bendroflumethiazide.
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26
Q

What are the side effects of SABAs?

A

Tachycardia, palpitations, fine tremor, headache, muscle cramps and hypokalemia

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27
Q

Give examples of antimuscarinics bronchodilators?

A

Ipratroprium/ tiotropium bromide

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28
Q

What is ipratropium bromide and how is it taken?

A

SABA. Non-selective muscarinic blocker. Nebulised for severe acute asthma or COPD. Maximal effect 30-60 mins.

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29
Q

What is tiotropium and its indication?

A

LABA.
Used for COPD management
More specific for the subset of muscarinic receptors commonly found in the lungs.

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30
Q

What are the side effects of anti-muscarinics?

A

Dry mouth, urinary retention, blurred vision, glaucoma

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31
Q

What drugs are used for airflow obstruction?

A

Bronchodilators (LAMA/LABA) combination inhalors

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32
Q

Which drugs are used for airway inflammation?

A

inhaled steroids

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33
Q

Why does salbutamol cuase tachycardia?

A
  • chemically related to adrenaline.
  • high doses can cause tachycardia and tremor due to weak agonism of beta 1 adrenoreceptor in cardiac tissue.
34
Q

What do blood eosinophils greater than or equal to 0.3 tell us?

A

Identifies and steroid responsiveness

35
Q

What are examples of glucocorticoids/ corticoidsteriods?

A

Fluticasone, budesonide

36
Q

What are the indications of fluticasone?

A

COPD. asthma, dermatoses

37
Q

What are the indications of budesonide?

A

Crohns disease, asthma, COPD, and more

38
Q

What are the short term effects of corticosteriods?

A

Decreased vasodilation and permeability of capillaries, decreased leukocyte migration to sites of inflammation.

39
Q

What is the MOA of glucocorticoids?

A
  1. inhibit neutrophil apoptosis and dmargination. inhibit phospholipase A2 which decreases the formation of arachidonic acid. they inhibit other inflammatory transcription factors and promote anti-inflammatory genes like IL-10.
40
Q

What is the difference between low dose and high dose glucocorrticoids?

A

low dose = anti-inflammatory effects
high dose = immunosuppressive (binds to mineralocorticoid receptors raising sodium and decreasing potassium levels.

41
Q

What are the advanatges and disadvanages of corticosteriods?

A

Advantages: fewer exacerbation
disadvantages: higher risk of pneumonia, oral thrush, high cost

42
Q

What is used to treat eosinophilic airway inflammation?

A

Corticosteroids

43
Q

Which three drugs make up the trimbow inhaler?

A

Formoterol (LABA)
Glycopyrronium (LAMA)
Beclometasone (ICS)

44
Q

What class of drug is theophylline?

A

methylxanthine, phosphodiesterase inhibitor

45
Q

What are the pharmacodynamics and side effects of theophyline?

A

Narrow therapeutic window (therapeutic dose close to toxic dose)
Max plasma conc - 10-20mg/L
Metabolised in the liver
Multiple drug reactions
SE - vomiting, cardiac arrhythmias, convlusions

46
Q

Give an example of a PDE4 inhibitor drug and its license

A

Roflumilast - selective PDE4 inhibitor
Licensed for COPD/Chronic bronchitis

47
Q

Explain the multisystem nature of CF.

A

The presence of the CFTR protein throughout the body including the lung, submucosal glands, pancreas, liver, sweat ducts, and reproductive tract

48
Q

What is the structure of the CFTR?

A

ATP-binding cassette transporter that functions as a ligand gated anion channel.
CFTR protein forms a membrane channel with 12 transmembrane domains (TM), two nucleotide-binding domains and a regulatory domain.
two membrane-spanning domains form a low-conductance chloride channel.

49
Q

What is the main function of the CFTR?

A

CFTR conducts chloride and bicarbonate and regulates sodium and water absorption across the epithelium

50
Q

What does the first three classes of mutation in CF lead to?

A

Complete loss of CFTR function

50
Q

How is CF caused and how many classes of mutations?

A

Mutation in the CF gene leads to a defect in the CFTR chloride ion channel. 7 classes of protein defect.

51
Q

What is a class I CFTR mutation?

A

Nonsense mutation with most causing premature stop codons and defective protein synthesis, leading to shortened CFTR protein which is defective.

52
Q

What is a Class II CFTR mutation and what is its prevalence?

A

Around 85%. Most common mutation is Phe508del. CFTR is poorly processed and is destroyed within the cell, resulting in little to no CFTR reaching the cell surface.

53
Q

What is a Class III CFTR mutation?

A

The CFTR protein forms a channel in the cell surface
- gate at the end of the channel doesn’t open and close at the right times.
- It reaches the cell surface but does not work and cannot transport chloride.

54
Q

What is a Class IV CFTR mutation?

A
  • CFTR reached the apical surface but the defective conduction of chloride throughout the channel results in poor CFTR function.
55
Q

What is a Class V CFTR mutation?

A

Decrease production of CFTR results in some production but insufficient to maintain normal function.

56
Q

What is a Class VI CFTR mutation

A

Significant plasma membrane instability.

57
Q

What is a Class VII CFTR mutation?

A

No RNA transcription.

58
Q

What occurs in a Phe508del mutation and what is its prevalence?

A

75%, most common. Class II mutation. Three base pair deletion in exon 10 of the CFTR gene results in the omission of phenylalanine at position 508 of the protein.
Results in abnormal folding, retention of the endoplasmic reticulum and degradation of the CFTR protein.

59
Q

Which drugs are effective in Phe508del mutation?

A

Correctors such as lumacafor or tezacafor help the CTFR protein fold correctly.

60
Q

What occurs in the G542X mutation?

A

2.5%, 2nd most common. Class I nonsense mutation. The codon for glycine (GGA) is mutated to a stop codon (TGA). No functional CFTR is produced.

61
Q

Which drugs are effective in G542X?

A

N/A
research is ongoing into ‘read-through compounds’ that could encourage the production of full-length CFTR mRNA and protein.

62
Q

What occurs in G551D mutation and what is its prevalence?

A

2%, 3rd. Class III. Glycine is replaced with aspartate at protein position 551. The abnormal CFTR reaches the cell surface but the channel doesn’t open properly.

63
Q

Which drugs are effective in G551D?

A

Potentiators such as ivacaftor can help the abnormal channel open.

64
Q

What is the impact of reduced CFTR function in CF?

A
  1. Reduced or absence of Na and Cl absorption results in excessive salt concentrations.
  2. Mucosal dehydration, defective CFTR-dependent bicarbonate and abnormal formation and release of mucus.
  3. Defective CFTR in the airways results in a reduced depth or airway surface liquid, altered biophysical properties of mucus and impaired mucociliary clearance.
  4. Increased bacterial adhesion and loss of bacterial internalisation. Bacterial colonisation promotes a perpetuating cycle of infection and inflammation which results in lung damage and progressive bronchiectasis.
65
Q

What happens to ions in normal physiology?

A
  1. Most of the NaCl is epithelial surface liquid reabsorbed. A large inward gradient means Na+ flows into the cell through epithelial epithelial Na+ channels (ENaC) in the apical membrane. The basolateral sodium pump then transported Na+ out of the cell and into the blood.
  2. Cl- is electrically attracted to Na+ and follows it by flowing CFTR Cl- channels in the apical membranes of the duct cells.
  3. The epithelium has a high conductance for ions and is thought to have a low permeability to water, allowing reabsorption of salt in excess of water. This results in the production of dilute surface liquid.
66
Q

What happens to ions in CF?

A
  1. The Cl- conductance is virtually abolished because CFTR is the only apical pathway for chloride.
  2. The sodium conductance also seems to be low as CFTR also activates ENaC. When Na+ attempts to flow out through remaining sodium-selective pathways, it is accompanied by Cl- and so it creates an excess of negative charge in the duct that attracts Na+ and prevents its further absorption.
  3. The net result is that very little NaCl is reabsorbed, resulting in a high salt content in CF epithelial surface liquid sweat.
67
Q

Which other body parts can CF affect?

A

ENT - chronic sinusitis, nasal polyps
Lungs - repeated LRTI, pneumothorax, haemoptysis
Skin - abnormal swear secretions (high Na+ and Cl-)
Hepatobiliary - liver disease, gallstones, portal hypertension
Endocrine - pancreatic insufficiency, CF related diabetes
Reproduction - male infertility
GI- steatorrhoea, distal intestinal syndrome, volvulus intussusception, rectal prolapse
Ortho- osteoporosis, Cf arthropathy

68
Q

How is sweat used to diagnose CF?

A

In CF, sweat contains high concentrations of sodium and chloride. The sweat is a key part of CF diagnosis. - A sweat chloride of greater than 60mmol/L is characteristic of CF.

69
Q

How are CT scans used for CF?

A

CT is a sensitive tool for identifying progression and characterising the extent of mucus plugging, bronchiectasis, and gas trapping in the lungs.

70
Q

What is the prevalence of lung disease in patients with CF?

A

Lung disease accounts for the majority of morbidity and mortality in patients with CF, with respiratory failure accounting for 85% of deaths.

71
Q

What can still happen in asymptomatic infants with CF?

A

Airway inflammation, infection, and lung damage.

72
Q

What is the prevalence of endocrine issues in patients with CF and how is this assessed/treated?

A

Most CF patients are pancreatic insufficient. Assessed using faecal elastase in stool.
CF-related diabetes occurs in up to 50% of adults Early diagnosis and insulin have a profound impact on patients wellbeing and survival.

73
Q

What is the prevalence of male fertility issues in patients with CF and how is this assessed?

A

The majority of male patients with CF are infertile due to blockage and failure to develop the vas deferens.
Semen analysis can be a useful diagnostic tool in more complicated cases.

74
Q

What is the impact on the life of someone with CF?

A
  1. High burden of disease - frequent hospitalisation to treat reoccurring infections and inflammation.
  2. Daily drug regimen (50-75 pills/day) e.g. antibiotics, bronchodilators, DNAase enzymes, hypertonic saline, pancreatic enzymes. Airway clearance therapy.
  3. Lung transplantation?
  4. Median life expectancy: 41 years.
75
Q

What are the aims of conventional treatment for CF?

A
  • protect lungs, reduce complications, treat infections and inflammation before significant lung damage.
    multidisciplinary approach: regular monitoring, conventional therapy including pancreatic replacement, nutrition support, regular exercise, antibitoics
76
Q

Why is gene therapy for CF disappointing?

A

delivering CF geen into airways of patients using viral vector can be challenging

77
Q

What are the 3 types of CFTR modulating drugs for CF?

A

Correctors, Potentiators, and amplifiers.

78
Q

What do CFTR correctors do and give examples.

A

Help the CFTR protein form the right 3D shape, increasing quantity of CFTR delivered to the cell surface, facilitating increased chloride transport. Helpful for Class II mutations.
e.g. lumacaftor, tezacaftor, elexacaftor

79
Q

What do CFTR potentiators do and give examples.

A

Facilitate increased chloride transport by potentiating the channel-open probability of the CFTR at the cell surface. Helps patients with gating and conduction mutations in the CFTR (Class III).

80
Q

What do Amplifiers do and give examples.

A

Increase amount of CFTR protein a cell makes. Many CFTR mutations produce insufficient CFTR protein. If the cell makes more CFTR protein, the potentiators and correctors would be able to allow even more chloride to flow across the cell membrane.
Amplifiers are being developed and tested and are not yet available.

81
Q

What are possible paths for future CFTR drug development?

A
  1. Determine the 3D structure of CFTR and apply structure-based drug design
  2. Do high throughput screening (HTS) using phenotypic assays
  3. Try to repurpose existing drugs or drugs in advanced development.

Therapeutics (7 decks)

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