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Respiratory/Musculoskeletal > Ph- Asthma > Flashcards

Ph- Asthma Flashcards

1
Q

What is the pathogenesis of asthma due to?

What are the 3 major cell types that infiltrate the lung of asthmatic patients?

A

It is due to persistent low-level inflammation of the airways caused by release of cytokines and inflammatory mediators by resident mast cells and infiltrating cells.

The airways are filled with:

  1. eosinophils
  2. neutrophils
  3. lymphocytes
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2
Q

Describe the acute response of asthma.

A

Allergens (via IgE) or non-specific stimuli (directly) activate sensitized mast cells and cause degranulation.

  1. Preformed mediators (histamine, heparin, proteases) are released
  2. LTs, PGs, and PAF are synthesized and released

Immediate inflammatory response occurs with:

  1. bronchoconstriction
  2. vascular congestion
  3. edema
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3
Q

Describe the chronic response of asthma.

A

Chemotactic factors released by mast cells and macrophages in the acute response attract other inflammatory cells from circulation into the airway epithelium.
Eosinophils, basophils and lymphocytes release additional bronchoconstrictor substances 6-10 hours after the acute attack,

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4
Q

What cytokines are released by T lymphocytes in asthma?

A
  1. IL3- mast cell survival
  2. IL4 and IL 13 (b cell switch to IgE and express adhesion molecules)
  3. IL5 - eosinophil differentiation and enhancement
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5
Q

What are the 3 main areas drug therapy for asthma target?

A
  1. bronchodilators - to relax airway smooth muscle
  2. reducing release of inflammatory mediators
  3. reducing activity of inflammatory mediators
    (2 and 3 are achieved via anti-inflammatory drugs)
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6
Q

Why are asthma drugs administered via aerosol delivery?

A

Produces high local concentration at the site of action (lungs) with minimal involvement of systemic circulation (minimizing side effects).

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7
Q

Under the best conditions, how much of inhaled drugs make it to the lungs?
What does this imply for drug design?

A

10%. The other 90% is swallowed so you want to design drugs that are:

  1. poorly absorbed by the GI
  2. inactivated by first pass hepatic metabolism
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8
Q

What are the 2 places b2 adrenergic agonists exert their effects?
What do they do?
What type of asthma are they able to treat?

A
  1. airway smooth muscle- relaxation
  2. inflammatory cells- inhibit mediator release

B2 agonists are used for acute/intermittent asthma. They are ineffective at reducing airway hypersensitivity in chronic asthma

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9
Q

What is the major short-acting B2 agonist?

What is the onset of action? When is max effect achieved? When does it stop working?

A

Albuterol is used to treat acute bronchospasms. It is inhaled (but oral forms are available too)

Onset of action: 1-5 minutes
Max effect: 30 minutes
Duration of action: 2-6 hours

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10
Q

How does albuterol/salmeterol inhibit mediator release from mast cells?

A

Mast cells have a high resting potential and need to hyperpolarize to release granules.
B2 agonists close K+ channels and inhibit the release of the granules

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11
Q

What is the molecular mechanism by which b2 agonists work? What type of receptor do they bind? What are the intracellular effects?

A

B2 agonists bind Gs which increases adenyl cyclase–> increased cAMP–> PKA

PKA inhibits myosin light chain kinase which relaxes bronchial smooth muscle
PKA closes K+ channels, not allowing mast cells to hyperpolarize to degranulate

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12
Q

What is the role of PDE4?

A

It inactivates cAMP so there is no PKA to inhibit myosin light chain or inhibit mediator release

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13
Q

What is the long acting B2 agonist?
What form of asthma is it used to treat?
What is the onset of action? How long do effects last?

A

Salmeterol sticks to the bilayer with a hydrophobic tail and thus are slow to diffuse away from the receptor.

Moderate persistent/severe asthma (with inhaled glucocorticoids)

Onset of action: 2-4 hours
Duration : over 12 hours

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14
Q

What is salmeterol contraindicated for? Why?

A

It is contraindicated for monotherapy of asthma because it helps bronchodilate but has little effect on inflammation.
It should be used with a steroid (inhaled glucocorticoid)

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15
Q

What type of asthma are glucocorticoids used to treat?

What patients are inhaled glucocorticoids recommended for?

A

They are anti-inflammatory and are used to treat chronic asthma (moderate and severe).
They are recommended for any patient who requires a short acting B2 (albuterol) more than once a day.

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16
Q

What is the molecular mechanism by which glucocorticoids work?

A
  1. They diffuse across the target cell membrane and bind to a glucocorticoid receptor in the cytoplasm.
  2. Receptor dissociates from heat shock proteins and immunophilin
  3. Free receptor goes into the nucleus where it binds/inhibits pro-inflammatory TFs (NFkB, AP1 via fos/jun dimer) and binds/activates anti-inflammatory genes (B2 receptors, MAPK phosphatase)
17
Q

Brochial biopsies showed a decreased in what 3 cells in the submucosa following glucocorticoid use?
In addition to inhibiting transcription of pro-inflammatory genes what else do glucocorticoids do?

A

There is a decrease in T cells, mast cells and eosinophils.

In addition to blocking transcription, there is:

  1. decrease in cell accumulation
  2. blocked macrophage Fc receptors
  3. inhibition of cytokines
18
Q

What is the major inhaled glucocorticoid and how is it used?
What is it frequently used in combination with?
What is the onset of action?

A

Fluticasone is used prophylactically to control asthma. They cannot reverse acute symptoms!

They are frequently used in combination with inhaled b2 agonist salmeterol to treat chronic persistent moderate/severe asthma

Onset of action is one week and there is continued improvement over months.

19
Q

Although infrequent and dose dependent, what are some of the systemic side effects associated with inhaled corticosteroids?

A
  1. oropharyngeal candidiasis
  2. decreased bone density
  3. thinning of skin
  4. purpura
  5. dysphonia
20
Q

What are the oral and systemic glucocorticoids?
What are they used for?
What is their onset of action?
What are the important side effects of this drug?

A

Prednisone is used to manage severe asthmatic episodes that take several days to resolve.
It has delayed onset of action (6-12 hours) but is ESSENTIAL for severe chronic attacks.

Side Effects:

  1. acute adrenal insufficiency from rapid withdraw of the drug
  2. long list of potential problems for continued use
21
Q

What is the mechanism of action of cromolyn sodium and nedocromil sodium?
What are the therapeutic uses?
What is the adminstration route, onset of action, and clearance?
What are the side effects?

A

They are inhibitor of mast cell release/degranulation reducing the responsiveness of inflammatory cells.

They are used prophylactically to reduce long term bronchoconstriction induced by allergens and exercise.
They are administered via inhalation and reach peak concentrations in 15 minutes. They have a 100 minute half life

Side effects:

  1. bronchospasm
  2. cough, laryngeal edema
  3. joint swelling
  4. angioedema
  5. headache
  6. rash
  7. nausea
22
Q

What are the 3 major leukotriene inhibitors?

What does each act on specifically?

A
  1. Zafirlukast- competitive antagonist of cysteinyl leukotriene receptor type 1
  2. Montelukast- competitive antagonist of cysteinyl leukotrience receptor type 1
  3. zileuton - 5 lipooxygenase inhibitor
23
Q

What is the mechanism of action of zafirlukast and montelukast?
What are the normal actions of the receptor they block?

A

They are competitive antagonists to cysteinyl leukotriene receptor type 1. This receptor (LTCys1) couples to Gq which causes:

  1. smooth muscle contraction.
  2. mucus secretion
  3. capillary permeability (edema)
  4. eosinophil recruitment
24
Q

Why can aspirin exacerbate asthma?

A

Because it is blocking the cyclooxygenase pathway, more arachadonic acid is pushed down the leukotriene pathway.
LTCys1 is a bronchoconstrictor

25
Q

What are the 3 main actions of LT inhibitors?

A
  1. antagonize and reverse asthmatic bronchospasm
  2. decrease airway hyperresponsiveness (zileuton)
  3. decrease airway inflammation
26
Q

How are the LT inhibitors taken?
When is onset of action?
How are they cleared from the body?

A

They are taken orally and are rapidly absorbed in the GI tract and metabolized in the liver (p450s)

Peak action: 1-4 hrs

27
Q

What are the adverse effects of:

  1. zafirlukast
  2. montelukast
  3. zileuton
A
  1. GI disturbances, mild headaches, increased aminotransferase activity
  2. very few
  3. Liver alanine aminotransferase activity increases to 3x normal; symptomatic hepatitis; dyspepsia
28
Q

When is the only real time you can justify using a LT inhibitor?

A

If there are safety concerns with inhaled glucocorticoids.

29
Q

What is the mechanism of action of theophylline?

A

Theophylline is thought to:

  • inhibits cellular cyclic nucleotide phosphodiesterase (so there is more cAMP to make PKA to relax bronchial smooth muscle) AND/OR
  • competitively antagonize adenosine receptors (which are inhibitors of adenyl cyclase which makes cAMP)
30
Q

What are the major effects of theophylline?

How is it absorbed? What is the half life? How is it eliminated?

A

relaxation of bronchial smooth muscle via increased cAMP–> PKA

It is absorbed from the GI tract, half life 3-7 hours, excreted hepatically

31
Q

What are the adverse effects of theophylline?

A
  1. GI distress—> emesis
  2. anxiety—>convulsions
  3. insomnia/headache—-> delerium
  4. cardiac rhythm disturbances (tachy, extrasystole)
32
Q

When is the only real time you might use theophylline over inhaled corticosteroid and b2 agonists?

A

It is very inexpensive so it is used in a lot of poor countries

33
Q

What asthma drug is an IgE inhibitor?
What is the mechanism of action?

What is the major benefit of this biologic?

A

Omalizumab- recombinant humanized monoclonal antibody against the Fc region of IgE so it cannot bind to FcReceptors on mast cells and basophils.

  • It is able to neutralize 95% of free IgE
  • it decreased the number of cell surface FcR on mast cells and basophils

It reduces EARLY and LATE phases of asthmatic response so it reduces:

  1. number of asthma exacerbations
  2. doses of inhaled corticosteroids
  3. improved quality of life
34
Q

How is omalizumab absorbed? What is the half life and how is it excreted?

What effects how dose is determined?

A

Subcutaneous injection every 2-4 wks
Half Life : 26 days
Elimination : liver

Dose is determined by body weight and total serum IgE levels. You need enough drug to neutralize 90%

35
Q

What are the adverse effects and toxicities of omalizumab?

A
  1. injection site reaction (redness, stinging, bruise)
  2. anaphylactic reaction (0.1%)
  3. increased cancer risk (0.5% vs 0.2% in control)
36
Q

Who is omalizumab currently indicated for?

A

Adults and children >12 with moderate to severe persistent allergies and/or asthma

37
Q

According to NIH, what drugs are recommended for:

  1. quick relief of asthma
  2. mild intermittent
  3. mild persistent
  4. moderate persistent
  5. severe persistent
A
  1. albuterol (b2 agonist)
  2. no daily medication
  3. anti-inflammatory (fluticasone, cromolyn, nedocromil)
  4. inhaled steroid (fluticasone) or fluticasone AND salmeterol (long acting b2 agonist)
  5. inhaled steroid AND salmeterol both in high doses

Respiratory/Musculoskeletal (36 decks)

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