Term
| How does the pathophysiology of airway obstruction in COPD and asthma differ? |
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Definition
1) In COPD, airway obstruction due to chronic bronchitis or emphysema is slowly progressive and largely irreversible
**Low FEV1 value that fails to respond to bronchodilators
** Inflammatory component is resistant to steroid therapy
2) In Asthma, chronic contraction of airway smooth muscle leads to REVERSIBLE airflow obstruction that is responsive to bronchodilators and corticosteroids. |
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Term
| What agents are responsible for the early and late responses in asthma? |
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Definition
1) EAR involves immediate bronchoconstriciton and vascular leakage from histamine, tryptase, LT and PGE release from mast cells.
2) Cellular infiltration and mucous hypersecretion in LAR (2-8h later) are mediated by Th2 lymphocytes that produce GM-CSF, IL-4, 5, 13, recruiting eosinophils (4,5) and stimulate IgE production by B cells.
**Bronchoconstriction seems also to be related to neural or humoral pathways.** |
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Term
| What are the 2 major categories of agents used to treat Asthma and COPD? |
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Definition
1) Bronchodilators (B2, methylxanthines and anti-cholinergics)
- Mainstay for COPD, and also used with inhaled corticosteroids to enhance relief by unknown mechanisms.
2) Anti-inflammatory drugs (glucocorticoids, LT inhibitors and receptor antagonists, mast cell-stabalizing agents or cromones).
- Effective in chronic asthma, and when combined with B2 agonists for symptomatic release |
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Term
| Why is it important for therapeutic particulates in aerosol delivered drugs to be 1-5 um? |
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Definition
Remember to hold your breath long enough for deposition.
1) >10 um are deposited in mouth and oropharynx only (Upper tract)
2) <0.5 um are inhaled to alveoli and exhaled without being deposited in lungs. |
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Term
| What are the 3 major categories of bronchodilators and how do they work? |
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Definition
1) B-adrenergic agonists
- Produce bronchodilation by stimulating B-2 receptors in smooth muscle, leading to cAMP-PKA phosphorylation of Ca-activated K channels (BKca) that relax smooth muscle by increasing K+ efflux and stimulating Ca sequestration)
- also inhibit ACUTE inflammation by inhibiting mast cell mediator release, preventing microvascular leakage and airway edema and enhancing mucociliary clearance.
2) Theophyllines (Methylxanthine)
- Weak, non-selective PDE inhibitor that produces increased cAMP and cGMP and inhibits adenosine receptor activation.
- Rarely used in developed countries because of dosing difficulties, but useful for severe asthma/COPD in patients unresponsive to B2-agonists.
3) Anticholinergics
- Inhibit M3 receptor activation and cGMP-mediated bronchial smooth muscle contraction |
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Term
| What is the preferred B2-agonist for rapid symptomatic relief of dyspnea associated with asthmatic bronchoconstriciton? |
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Definition
| Short-acting, beta selective drugs like Albuterol (vs. long-acting Salmeterol and Formoterol) |
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Term
| Why is the development of more selective B2-agonists not warranted clinically? |
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Definition
Side effects are due to B2 activation in peripheral tissues (Cardiac arrhythmias, muscle tremors, CNS effects and metabolic disturbances at supra-therapeutic doses).
Making it MORE selective would do nothing about this (tissue-specific would be another story). |
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Term
| Why is tolerance to long-acting B agonists (LABA) like Salmeterol and Formoterol not observed, despite the tendency of B-adrenergic receptors to be desensitized upon chronic agonist treatment? |
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Definition
| Spare receptors in airway smooth muscle and low expression of GRK2 (kinase that phosphorylates and inactivates these receptors) |
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Term
True or False:
LABA use is currently recommended in combination with ICS |
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Definition
| True, despite ongoing long-term safety evaluations |
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Term
| How can B2 adrenergic receptors produce PRO-inflammatory responses. |
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Definition
Alternate signaling through receptor coupling with Gq or Gb
1) Gq
- PLC activation
2) Gb
- B-arrestin-2 activation and p38 MAPK and P13k signaling
Current trials are underway to evaluate Nadolol as a beta-clocker that acts an as an inverse agonist (selective inhibition of constitutively active beta-2 receptor coupled to beta-arrestin-2 or Gq) |
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Term
| What is the differential expression pattern of M1,M2 and M3 receptors in the airways and what are the clinical consequences of this distribution? |
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Definition
1) M1 present on peribronchial ganglion sites where preganglionic nerves transmit to postganglionic nerves
2) M2 found on pre-ganglionic sites and function to inhibit ACh release
3) M3 are found on smooth muscle and are coupled to Gq: coupling leads to increased intracellular Ca and contraction.
**Atropine and Ipratropium compete with ACh for M3 receptor sites |
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Term
| Why might Tiotropium be preferred to Ipratropium to treat COPD? |
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Definition
NOT USED in asthma
Both bind to all M receptors with high affinity and are given in inhaler.
Tiotropium dissociates from M3 more slowly than Ipratropium (prolonged effect), but quickly from M2, limiting its antagonism of pre-jucntional inhibition of ACh release. |
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Term
True or False:
Anticholinergic drugs like atropine, ipratropium and tiotropium are most effective in treating severe asthma. |
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Definition
False!
They are used in airway obstruction in COPD, to inhibit reflex increases in parasympathetic activity that contribute to bronchoconstriction. |
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Term
How might each of the following be useful to treat Asthma and COPD in the future?
1) Vasoactive intestinal peptide analogs
2) PGE2
3) ANP
4) PDE4 inhibitors
5) Pharmacogenomics |
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Definition
1) Stable cyclic analogue of VIP relaxes constricted airways when given by inhalation to asthmatic patients.
2) Bronchodilator/anti-inflammation in specific lung-receptor subtypes?
3) ANP itself is broken down quickly, but related peptide URODILATIN produces bronchodilation and protects against constriction
4) Similar to theophylline, but causes emesis right now
5) down-regulation of 16th amino acid in B2 adrenergic receptor may influence responsiveness to B-agonists. |
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Term
What are the anti-inflammatory/immunomodulatory effects of corticosteroids on each of the following cell types?
1) Macrophages and Monocytes
2) Endothelial cells
3) Basophils
4) Fibroblasts
5) Lymphocytes |
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Definition
1) Inhibit AA metabolism, cytokine production/release and acute phase reactant production
2) Inhibit ELAM-1 and ICAM-1, suppressing leukocyte localization. Also inhibit release of acute phase reactants, cytokines and AA derivatives
3) Inhibits IgE-dependent release of histamine and LTC4
4) Suppress growth-factor-inudced DNA synthesis and proliferation
5) Inhibit cytokine release |
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Term
| What are some of the major adverse effects of corticosteroid use? |
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Definition
1) HPA suppression at high doses
2) Bone resorption
3) Carbohydrate and lipid metabolism abnormalities
4) Skin thinning
5) Purpura
6) Dysphonia
7) Candidiasis
8) Growth retardation. |
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Term
| How do glucocorticoids act to inhibit inflammation (i.e. mechanism)? |
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Definition
1) Bind GR which is a nuclear receptor that regulates gene transcription, repressing pro-inflammatory genes in multiple cell types
** activates genes by recruiting HATs (loosening DNA)
** represses genes by recruiting HDAC (tightens grip)
2) Bound GR Inhibits NF-kB and AP-1 |
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Term
| What effect on potency can structural modifications of cortisol have? |
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Definition
| Enhance half-life and increase/potency and efficacy of Glucocorticoid activity. |
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Term
How are glucocorticoids delivered in asthma treatment?
How are side effects minimized? |
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Definition
1) Aerosol delivery is preferred to avoid systemic side effects, especially in less severe, chronic asthma.
2)
- Some oral bioavailability still present (goes to gut)
- Pulmonary retention limits systemic circulation and is increased by Lipid conjugation (lipophilicity correlate with lung retention)
**Watch out of skin thinning, oral candidiasis and dysphonia** |
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Term
| How does Fluticasone Propionate (active component of FLOVENT) treat asthma? |
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Definition
Glucocorticoid analogue that is subjected to rapid inactivation in liver, so side effects are minimized
1) Work in lungs first
2) In circulation, P450 3A4-mediated breakdown to 17-b-carboxylic acid drastically lowers systemic effects |
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Term
Why might you give Ciclesonide to treat asthma?
Why give it instead of Fluticasone proprionate? |
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Definition
1) Novel GR agonist with high pulmonary deposition compared to fluticasone proprionate, that is preferentially activated in lungs compared to the oropharynx, where they are esterified and inactivated.
**Esterases are present in other tissues, so watch out for systemic side effects**
2) Better pulmonary deposition, but chance of systemic side effects (oral bioavailability is comparable, however). |
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Term
| What is Advair and why is it used? How does it work? |
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Definition
1) Glucocorticoid/LABA combination in single inhaler.
2) LABA may increase nuclear localization of GR and steroid may effect B2 receptors.
**HOWEVER, glucocorticoids can cause pro-infammatory effects if they enhance B2-Gs coupling |
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Term
| What are "dissociated" glucocorticoids and how might they be used to treat asthma? |
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Definition
Unleash gene repression activity of GR while having little impact on gene activation of the receptor (Get the HDACs moving without increasing the HATs)
Hoped to maintain anti-inflammatory properties while minimizing side effects. |
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Term
| What kinds of new therapies are being developed to avoid issues with patient compliance for inhaler use? |
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Definition
1) Very-long acting B2-agonists (Indacaterol) that have quick action, broad therapeutic windows and limited SE.
**Maybe in combination with glucocorticoids** |
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Term
| What is glucocorticoid resistance and why is it a problem? How should these patients be treated? |
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Definition
1) Corticosteroid-dependent (CD asthma) results in a situation of reduced responsiveness among SMOKERS that requires very high doses (You can't lower them, but high doses aren't enough!)
Rarely, it can be totally resistant (CR)
2) CD and CR forms of asthma changes to GR function such as reduced nuclear transcription of GR or disruptions in histone modifications
- Increased GRb expression (as opposed to active GRa form) may also contribute.
3) Long-acting inhaled B2-agonists or Theophyllines |
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Term
| Why is it thought that Theophyllines are effective in treating corticosteroid-resistant asthma? |
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Definition
| Decreasing chromatin-assicaited histone protein acetylation by increasing HDAC. |
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Term
| What drugs other than corticosteroids are available to treat eosinophilia and related pathogenesis in asthma? |
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Definition
May be important for patients taking inhaled corticosteroids with poorly controlled asthma.
Cromones, anti-LT and anti-IgE
1) Cromones in PEDIATRICS
- Phosphoryate cell membrane proteins that terminates mast cell release
- Suppress firing of C-fiber nerve endings (J receptors?)
- Inhibit inflammatory cells
- Inhibit IgE production by B lymphocytes
- Chloride channels in mast cells and sensory neurons
2) Anti-Leukotrienes
- Prevent bronchospasm by either inhibiting 5-LOX (Zileutin) or blocking cysLR activity (Zafirlukast and Montelukast)
3) Omalizumab (anti-IgE) recombinant humanized monoclonal Ab.
- Prevents IgE receptor binding (FcR1) on mast cells and stops cross-linking and de-granulation ($$$$) |
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