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PED2006: Systems Pharmacology > Theme 2: The Respiratory System (L3) > Flashcards

Theme 2: The Respiratory System (L3) Flashcards

1
Q

How is asthma characterised?

A

As a reversible airflow obstruction
Airway inflammation
Airway hyper responsiveness

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2
Q

What is obstruction caused by in asthma?

A

Smooth muscle contraction
Inflammation
Edema (fluid)
Mucus
Airway structural changes

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3
Q

What are the acute symptoms of asthma?

A

Acute exacerbations (asthma attacks)

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4
Q

What are the major symptoms of asthma?

A

Wheezing
Chest tightness
Dyspnea
Cough
Hypoxemia

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5
Q

What are the main cells present in inflamed airways?

A

Eosinophils and neutrophils

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6
Q

What changes occur in the airways during chronic asthma?

A

Oedema
Dilated BVs
Mucus
Eosinophils and neutrophils accumulate

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7
Q

What are the two acute phases of asthma?

A

Immediate and late

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8
Q

What is the immediate phase of asthma?

A

Stimulus - triggers attack
Mast cells and mononuclear cells accumulate
Spasmogens, cysLTs, H and PGD2 - bronchospasm
Chemotaxins and chemokines released

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9
Q

What is the late phase of asthma?

A

Chemotaxins and chemokines allow infiltration of cytokines releasing Th2 cells and monocytes + inflammatory cells (eosinophils)
Mediators e.g. cysLTs, neuropeptides, NO, adenosine and EMBP, ECP
Epithelial damage
Airway inflammation and airway hyper-reactivity
Bronchospasm, wheezing and coughing

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10
Q

How can bronchospasm be pharmacologically stopped?

A

Beta2-adrenoreceptor agonists, cysLTs-receptor antagonists and theophylline

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11
Q

Which co factors of a late phase asthma attack are toxic to the epithelium?

A

Eosinophil cationic protein
Eosinophil major basic protein

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12
Q

What are the properties of a late stage in asthma?

A

Airway sensitisation then exposure leads to airway obstruction
Early acute - Bronchoconstriction
Late delayed - inflammation, hyperresponsiveness
Chronic - airway damage and remodelling

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13
Q

What are the main pathways we need drugs for?

A

Relaxation of smooth muscle
Blockage of inflammatory cascades

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14
Q

Which drugs are required for relaxing smooth muscle?

A

Beta agonists
PDE blockers
Leukotriene receptor antagonists

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15
Q

Which drugs are required for blocking inflammatory cascades?

A

Corticosteroids
Leukotriene receptor antagonists
PDE blockers
Targeted biologics

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16
Q

What are the mechanisms of beta2 receptor agonists?

A

Relax smooth muscle in the airway increase cAMP using GPCRs - PKA

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17
Q

What are examples of beta2 adrenoreceptor agonists?

A

Adrenaline - non-selective
Isoprenaline - selective, bronchodilation and cardiac stimulation

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18
Q

What are the routes of administartion for beta2 adrenoreceptor agonists?

A

Inhalation - inhaler
solution or powder
Oral
Parenteral - IV, SC or IM

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19
Q

What are examples of short acting beta2 adrenoreceptor agonists?

A

Salbutamol, terbutaline
Acute episodes
Inhalation
3-5h duration

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20
Q

What are examples of long-acting beta2 adrenoreceptor agonists?

A

Salmeterol, formoterol
twice daily
~12h duration
lipophilic structure aids duration
adjunct to corticosteroids

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21
Q

What are the side effects of beta2 adrenoreceptor agonists?

A

Minimised delivery with inhalation
Muscle tremor high doses
Tachycardia
Cardiac dysrhythmias
Risk of paradoxical bronchospasm

22
Q

What is SRS-A?

A

Its is an antigen induced effects using slow-reacting substance of anaphylaxis which was believed to be the major cause of allergic asthma

23
Q

What was SRS-A found out to be?

A

Leukotrienes which are products of arachadonic acid

24
Q

Where are leukotrienes produced from?

A

Mast cells

25
What are the main leukotrienes in asthma?
Cysteinyl LTs (LTC4 and LTD4) Constrictors of bronchial smooth muscle Increase vascular leakage and mucus production Chemoattractants for eosinophils/basophils Cys-LT1 receptor coupled to Gq - Ca2+ LTB4 potent chemoattractant for neutrophils
26
What are the 3 approved drugs approved for use in asthma?
leukotrince receptor antagonists (zafirlukast and montelukast) 5-lipoxygenase inhibitor (zileuton) Others in development (5-LO inhibitors, cPLA2 and FLAP)
27
Where do both zafirlukast and montelukast work?
Block LTC4 and LTD4 on smooth muscle Block some cys-LT inflammatory actions Do not block LTB4 effects
28
What is Zileuton's mode of action?
It is a potent and selective inhibitor of 5-LOX Inhibition of all 5LOX products from LTA4 synthesis Lt effects via cys-LT2 receptors
29
What are the leukotriene modular indications?
No production of rapid bronchodilation -weak anti-inflammatory
30
How are leukotriene modulators used clinically?
Mild to moderate asthma - improve basal lung function and symptoms; alternative low dose Severe asthma - not effective if patient not controlled on ICS + LABA
31
What are the contraindications of leukotriene modulators?
Asthma: prophylaxis and chronic treatment Montelukast: adults, children >6 months acute prevention of exercised-induced bronchconstriction allergic and perennial rhinitis Zafirlukast: adults, children >5 years Zileuton: adults, children >12 years
32
Why may people respond and not respond to LTAs?
Polymorphisms in 5-LOX, LTC4 synthase or cys-LT1 receptors Responders - NICE guidelines when MART (Maintenance and Reliever Therapy) is sufficient
33
What are antimuscarinic treatments of asthma?
Ipatropium and tiotropium M3 antagonist -bronchodilation and reduce mucus secretion Used as adjunct therapy to beta2 agonists and steroids Increase mucocilliary clearance through action on cilia COPD
34
How do muscarinic antagonists act as bronchodilators?
Parasympathetic nerves synthesise and release ACh and are primary source of ACh in lung Innervate conducting airways from trachea to bronchioles and pulmonary blood vessels
35
What are SAMAs?
Short acting muscarinic antagonists Ipratropium bromide Slow onset persist for 6-8h
36
What are LAMAs?
Long acting muscarinic antagonists Tiotropium bromide Gycopyrronium bromide Umeclidinium bromide Aclidinium bromide Non-selective receptor blockade
37
What are the side effects of SAMAs and LAMAs?
Dry mouth gastrointestinal motility disorder Tachycardia Nausea
38
Which treatments focus on immunosuppression in asthma?
Inhaled corticosteroids Biologics
39
How do corticosteroids work?
Inhibit inflammatory response to injury and allergens Inhibit synthesis of: Cytokines cell chemoattractants vasoactive agents dec. inflammatory cell infiltration, proliferation, vascular permeability and mucus secretion
40
How do glucocorticoids inhibit NFkB?
It is a TXN factor for inflammatory cytokines Transrepression of NFkB major anti-immune effects of GCs SGR complex inhibits HAT and HDAC2 HDAC2 deacetylates and represses genes
41
What are the inhaled corticosteroids?
Beclametasone and budesonide
42
What do corticosteroids reduce?
TXN of: Th2 cytokines Activation eosinophils IgE Leukotrienes and platelet activation factor COX pathway
43
How long do corticosteroids take for effect?
Sometimes a full week
44
What are the advantages of inhaled corticosteroids?
Reduced systemic side effects Direct Action on the Airways Effective Inflammation Control Reduce Asthma Exacerbations Steroid-Sparing Maintenance of Long-Term Asthma Control Safe for Long-Term Use
45
What are the disadvantages of inhaled corticosteroids?
Cause adrenal suppression and reduced bone mineral density when taken long-term Inc. risk fungal infection (orophrangeal candidiasis) - need spacer
46
When are oral corticosteroids used?
Short term and severe episodes, severe acute asthma attacks
47
What are the different oral corticosteroids?
Prednisolone and hydrocortisone
48
What happens in prolonged oral corticosteroid use?
Suppression of immune response Cushings Osteoporosis Hyperglycaemia Muscle wasting Inhibition of growth of children
49
What is the function of eosinophils in allergic asthma?
Main inflammatory cells in allergic asthma Recruited/activated mainly by IL-5 from Th2 Secrete: Th2 cytokines ROS LTC4/LTD4;PGD2 TGF-beta Major basic protein - antiparasitic
50
What are the different IL blockers?
Mepolizumab- mAb IgG1 Reslizumab - mAb IgG4 Banralizumab - IL-5Ralpha mAb IgG1 and FcRIII
51
What is the clinical efficacy and indication of IL-5 blockers?
Add-on maintenance for treatment eosinophilia asthma Reduces blood eosinophils Reduce exacerbations Glucocorticoid sparing effects Small increase in lung function

PED2006: Systems Pharmacology (5 decks)

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