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III > Asthma > Flashcards

Asthma Flashcards

1
Q

How prevalent is asthma?

A

> 5 million people receiving treatment
3 people per day die, 905 of deaths preventable
NHS spends £1 billion per year.
Most common long-term medical condition.

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2
Q

How does Asthma differ from COPD?

A

Asthma obstruction is often reversible, either spontaneously or with treatment.

COPD not reversible.

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3
Q

How does an asthmatic bronchiole differ from a normal bronchiole?

A

Increased smooth muscle contractility.
Hyperplasia - more muscle cells.
Hypertrophy - bigger muscle cells.
Smaller diameter as a result.

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4
Q

What regulators of smooth muscle growth are there?

A 
Mitogens: 
Platelet derived growth factor. 
Endothelin 
Cytokines
Histamine

Modulators:
Heparin
NO2
PGE2

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5
Q

How does the autonomic nervous system function in the airways of an asthmatic differ to normal patient?

A

Increased cholinergic tone.
Airways are innervated by the vagus: Cholinergic nerves: ACh acting on M3 receptors.
Excitatory non-adrenergic non-cholinergic transmitters (eNANC): activated by neurokinin A, neurokinin B, Substance P.

All stimulate GPCR leading to elevation of intracellular free calcium.

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6
Q

Are muscarinic agents used in mild/moderate asthma?

A

No

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7
Q

What may the loss of M2 receptor feedback cause?

A

Loss of feedback may lead to enhanced airway contraction because neuronal ACh release is inhibited by M2 receptor feedback.

Hence need for muscarinic antagonists which target only M3.

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8
Q

How do B2-adrenoceptor agonists cause bronchodilation?

A

Gas coupled AC activity.
Increased cAMP leading to PKA.
PKA leading to calcium sequestration and inactivation of MLCK.

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9
Q

Salbutamol is what type of drug?

A

Short-acting b2-adrenoceptor agonist

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10
Q

Formoterol is what type of drug?

A

Long-acting b2-adrenoceptor agonist

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11
Q

Salmeterol is what type of drug?

A

Long-acting b2-adrenoceptor agonist

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12
Q

Why are PDE inhibitors such as theophylline used in asthma?

A

Phosphodiesterase inhibitors prevent the breakdown of cAMP. (Usually done by PDEIII and PDEIV in smooth muscle)

Increased cAMP leads to bronchodilation.
Theophylline has a narrow therapeutic window.

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13
Q

What autonomic regulators favour bronchoconstriction?

A

Excitatory ones:
ACh on M3 receptors.
eNANC

Bronchodilation: 
Inhibitory:
Adrenaline
iNANC
NO
ACh (M2 receptors)
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14
Q

ACh acting on what receptors causes bronchoconstriction?

A

M3

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15
Q

ACh acting on what receptors causes bronchodilation?

A

M2. Neuronal ACh release is inhibited by M2 receptor feedback.

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16
Q

What are allergens?

A

Antigens that elicit an allergic response.

Not all allergics are asthmatic and not all asthmatics are allergic.

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17
Q

How do allergies develop?

A

Strong genetic influence.

Driven by T helper TH2 cells and their products (TH2 cytokines).

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18
Q

What effect do Th1 cytokines have on Th2 production?

A

Suppress Th production.
Allergic disease is associated with an imbalance of the Th1LTh2 cytokine ration.
Th1 are anti allergic, Th2 are pro allergic.

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19
Q

IFNg and IL-12 are produced by:

A

Th1 cells.

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20
Q

IL-4 and IL-13 have what?

A

Overlapping receptor usage and very similar actions, both produced by TH2

21
Q

What cytokines are produced by Th2 cells?

A

IL-4 + IL-13 (Very similar)
IL-5
IL-6

22
Q

What factors favour the Th1 phenotype?

A
  1. Presence of older siblings
  2. Early exposure to day care.
  3. Tuberculosis, measles, Hep A
  4. Rural environment.
23
Q

What factors favour the Th2 phenotype?

A
  1. Widespread use of antibiotics.
  2. Western lifestyle
  3. Urban environment
  4. Diet
  5. Sensitisation to house-dust mites and cockroaches.
24
Q

IL-4 and IL-13 cause B lymphocytes to do what?

A

Make IgE antibody,

The IgE antibody is a relatively rare immunoglobin in plasma which causes degranulation of mast cells.

25
Q

What are the effects of the IgE antibody?

A

Binds to mast cell surface via FceR.

Upon exposure of mast cell bound IgE antibody to antigen mast cell degranulation occurs.

26
Q

What does the IgE antibody cause?

A

Mast cell degranulation.
Binds to mast cell surface via FceR.
Upon exposure of mast cell bound IgE antibody to antigen mast cell degranulation occurs.

27
Q

What are mast cell products?

A 
Histamine,
Membrane-derived lipid mediators of inflammation. 
TNF and other cytokines. 
Proteases. 
Heparins.
28
Q

What influence do LTC4 and LTD4 have in asthma?

A

They cause potent constriction of airway smooth muscle and increase vascular permeability leading to oedema.

29
Q

What role does LTB4 play in asthma?

A

No direct bronchoconstriction.

Chemotactic for leukocytes,

30
Q

What role do the prostanoids play in asthma?

A

PGE2: airway smooth muscle relaxation. Decreased leukocyte activation. Sensitises irritant receptors - cough.

PGD2: chemotactic, bronchoconstrictor.

31
Q

What role does PGE2 play in asthma?

A

Airway smooth muscle relaxation, decreased leukocyte activation, sensitises irritant receptors.

32
Q

Eosinophil stimuli

A

Cytokines: IL-5, TNF, GM-CSF, IL-4, IL-13.
Lipid mediators: LTB4, PAF
Chemokines: eotaxin.

33
Q

Eosinophil products

A

Lipids: LTC4, PAF, TxA2.
ROS
Cationic proteins: MBP is an M2 receptor antagonist.

34
Q

Which leukotriene is chemotactic for leukocytes?

A

LTB4 does not cause bronchoconstriction.

35
Q

What is non-allergic (intrinsic) asthma?

A

30% adults non-allergic asthma,

Skin test negative but serum IgE levels are still elevated.

36
Q

What role does innate IL-13 play in virus-induced asthma?

A

Influenza infects body.
Il-33 production occurs.
Stimulate natural killer cells to produce IL-13

37
Q

Why does IL-13 lead to intrinsic asthma?

A

Increases eosinophil adhesion and migration.
Increases mucus secretion
Causes tissue remodelling (heparin??)
Increases airway smooth muscle contractility.
Switches B cells to the production of IgE causing Th2 skewing.

38
Q

Of the following B2-agonists which is the most lipophilic?
Formoterol
Salbutamol
Salmeterol

A

Salmeterol > formoterol > salbutamol.
Formoterol forms depot in lipid membrane and leaches out to interact with the receptor.

Salmeterol interacts with the membrane and diffuses laterally to bind receptor.

39
Q

How does theophylline function as an asthma treatment?

A

Phosphodiesterase inhibitor that inhibits the breakdown of cAMP by PDEIII and IV in the airway smooth muscle.

Increased cAMP leads to bronchodilation.

40
Q

How do glucocorticoids function in asthma treatment?

A

Act by regulating gene transcription: inhibit cytokine transcription and inhibit inflammatory leukocyte migration.

Promote eosinophil apoptosis.
Indirectly inhibit phospholipase A2 activity.

41
Q

Glucocorticoids function at what step in arachidonic acid metabolism?

A

Inhibit PLA2 so membrane phospholipid –X–> Arachidonic acid

42
Q

Which B2-agonist interacts with the cell membrane and diffuses laterally to bind the receptor?

A

Salmeterol.
Formoterol forms depot in lipid membrane and leaches out to interact with the receptor.

Salmeterol > formoterol > salbutamol.

43
Q

What is one leukotriene synthesis inhibitor?

A

Zileuton: inhibits 5-lipoxygenase

44
Q

What are two leukotriene receptor antagonists?

A

Montelukast

Zafirlukast

45
Q

What may be the future of asthma therapy?

A

Anti- IL-4
Anti - IL-13 receptor
Anti-TNFa

46
Q

What are Chromones (cromoglycates)?

A

Inhibit mediator release from lung mast cells.

Only effective in about half patients.

47
Q

What is omalizumab?

A

Monoclonal antibody which binds the Fc portion of IgE preventing IgE binding mast cells.
Protein drug which must be administered parenterally and is very expensive.

Approved for IgE mediated severe allergic asthma that is not responsive to glucocorticoids.

48
Q

What is one biological drug approved for IgE mediated severe allergic asthma that is not responsive to glucocorticoids?

A

Omalizumab:
Monoclonal antibody which binds the Fc portion of IgE preventing IgE binding mast cells.
Protein drug which must be administered parenterally and is very expensive.

49
Q

Excitatory non-adrenergic non-cholinergic transmitters (eNANC): are activated by what?

A

Excitatory non-adrenergic non-cholinergic transmitters (eNANC): activated by neurokinin A, neurokinin B, Substance P.

All stimulate GPCR leading to elevation of intracellular free calcium.

III (24 decks)

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