Respiratory Disorders Flashcards
asthma characteristics
- inflammation of airways
- bronchial hyper-reactivity
- reversible airways obstruction
- airways sensitive to stimulants
- bronchospasm, propagate chronic inflammation response
asthma pathophysiology (general)
- involves differentiation and activation of eosinophils, IgE production and release
- IgE receptor expression on mast cells and eosinophils
Immunoglobulin E, inflammatory mediators
asthma pathophysiology (immediate phase)
cause?
what cells release mediators?
what are some mediators involved? (2 things)
Bronchospasm
- initial response to allergen provocation
- mainly caused by spasm of bronchial smooth muscle
- allergen interaction with mast cell causes release of inflammatory mediators (histamine, leukotriene B4, prostaglandin D2, interleukins, tumor necrosis factor alpha)
- release of chemotaxins and chemokines attracts leukocytes (eosinophils) that propagate late phase
asthma pathophysiology (late phase)
what time?
which cells lead to the pathway?
what mediators are released
Inflammation
- primarily nocturnal
- a progressive inflammatory reaction
- Th2 lymphocytes (T helper lymphocytes) express cytokines (eosinophils) and secretes inflammatory factors and cells
- inflammatory cells (activated eosinophils) release cysteinyl leukotrienes, interleukins, other mediators that cause damage to and loss of epithelium
- inflammatory cells also release growth factors that cause hypertrophy and hyperplasia of airway smooth muscle cells
Bronchodilators (general)
purpose?
4 types
- reverse bronchospasm of immediate phase
1. B-adrenoceptor agonists
2. theophylline/aminophylline (caffeine like)
3. cysteinyl leukotriene receptor antagonists
4. muscarinic receptor antagonists (used for COPD)
Bronchodilators - B-adrenoceptor agonists
MOA (3 things)
- dilate bronchi via direct action of smooth muscle cell B2-adrenoceptors
- B2 adrenoceptors are G-protein coupled receptors that activate adenylate cyclase and increase cAMP levels (2nd messenger)
- increased cAMP generation leads to activation
of protein kinase A (PKA), reducing intracellular
calcium levels leading to bronchodilation - also inhibit mediator release from mast cells and TNFa release from monocytes
- increase mucus clearance (obstructs airway) by acting on cilia
Bronchodilators - B-adrenoceptor agonists
dosage form
- usually given by inhalation or aerosol, powder, nebulized solution
- in some cases, orally or via injection
Bronchodilators - B-adrenoceptor agonists
short acting
2 examples?
duration of action?
- salbutamol (ventolin)
- terbutaline
- 3-5 hours
- as needed basis to control symptoms, reach max effect within 30 min
Bronchodilators - B-adrenoceptor agonists
long acting
2 examples?
duration of action?
- salmeterol
- formoterol
- 8-12 hours
- usually taken as adjunctive therapy in pts with asthma inadequately controlled by glucocorticoids
salbutamol
terbutaline
Short acting B-adrenoceptor agonists
salmeterol
formoterol
Long acting B-adrenoceptor agonists
Bronchodilators - B-adrenoceptor agonists
side effects (3)
- tachycardia
- dysrhythmias
- tremor
peripheral vasodilation, hypokalemia, hyperglycemia
Bronchodilators - Theophylline/aminophylline
dosage form
MOA (inhibits 2 things + effect)?
- orally as a sustained-released preparation
MOA
- methylxanthine based agent
- inhibits phosphodiesterase (PDE), prevents breakdown of cAMP (increase cAMP levels)
- inhibits adenosine receptors (competitive antagonist)
- inhibits release of intracell. Ca2+ and thereby reduces smooth muscle contraction
Extra pharmacokinetics
- narrow therapeutic window
- metabolized by CYP450 enzymes
Bronchodilators - Theophylline/aminophylline
side effects (2)
cardio (*dysrhythmia) CNS toxicities (headaches and *seizures)
GI upset (nausea, vomiting) stimulatory effects (insomnia, restlessness)
Bronchodilators - cysteinyl leukotriene receptor antagonists
2 examples
MOA (which receptor in particular)?
efficacy compared to B2?
Montelukast
Zafirlukast
- derivative of arachidonic acid, Gq protein
- taken by mouth and usually in combo with inhaled corticosteroid
MOA
- antagonize CysLT1 receptor only
- reverses effects of bronchoconstriction, hyperresponsive airways, mucosal edema, mucous hypersecretion
- less effective than B2 agonists at relaxing airways (additive together)
- may reduce active rxns in aspirin sensitive patients
- pt hypersensitive to aspirin secrete more
leukotrienes and airways are more responsive
- pt hypersensitive to aspirin secrete more
Montelukast
Zafirlukast
Side effects (generalizations?)
Bronchodilators - cysteinyl leukotriene receptor antagonists
- mostly well tolerated
- headache, GI disturbances
- Zafirlukast inhibits CYP3A4 (may increase warfarin effects)
Anti-Inflammatory Agents - Glucocorticoids
Function?
Name 5 inhaled ones
Name 1 oral one
- prevent the progression of chronic asthma and are effective in acute severe asthma
- often used with B2-adrenoceptor agonists
Inhaled: (-asone, -ide)
- beclometasone
- budenoside
- flucticasone
- mometasone
- ciclesonide
Oral:
- prednisolone reserved for pt with severest disease
Anti-Inflammatory Agents - Glucocorticoids
MOA?
- general (1)
- 2 mechanisms to control gene expression (where do ligands bind to)
- bind intracellular receptors that then dimerize, allowing for nuclear translocation and modification of gene transcription (transcription factors)
- receptor can go into nucleus to modify transc
A. Basic transactivation
- ligand binds to GR dimer (glucocorticoid receptor) and upregulates transcription
B: Basic transrepression
- ligand binds to GR dimer, which binds a nGRE (negative glucocorticoid receptor response element) and turns off transcription
Anti-Inflammatory Agents - Glucocorticoids
MOA in asthma? (3)
What mediators do they reduce? (3-4)
- inhibit proliferation of Th cells by reducing the transcription of the IL-2 gene
- this leads to reduced formation of Th2 cytokines, reducing recruitment and activation of eosinophils
- inhibit allergen induced influx of eosinophils into lung (by decreasing IL-5, IL-13)
- IL-5 proliferates eosinophils to airways
- IL-3 activates mast cells - reduce production of IgE and expression of IgE receptors
Anti-Inflammatory Agents - Glucocorticoids
Adverse effects
Inhaled? (1)
Oral?
Is risk of systemic side effects high?
Inhaled steroids
- *thrush (oropharyngeal candidiasis): fungal overgrowth in mouth and throat due to T lymphocytes unable to fight off fungal infections
- dysphonia (croaky)
- adrenal suppression (children) mainly by beclomethasone and budesonide
Oral steroids
- increased risk of infection, hyperglycemia (gluconeogenesis, osteoporosis
Risk of systemic side effects low due to low sys absorption, bioavailability
Anti-IgE Treatment - Omalizumab
MOA?
Why is it used?
Dosage form?
Other uses?
- humanized monoclonal anti-IgE antibody binds to IgE and prevents interaction with IgE receptors
- severe allergic asthma that does not respond to high doses of corticosteroids
- adverse effects: anaphylaxis
- subq once every 2-4 weeks
- use in urticaria, allergic rhinitis, atopic dermatitis
- works only if IgE is not already bound to receptor
Omalizumab
Anti-IgE Treatment - severe allergic asthma that does not respond to high doses of corticosteroids
IL-5 Inhibition
Mepolizumab
Reslizumab
- humanized monoclonal antibodies that bind and inhibit IL-5 which differentiates and recruits eosinophils
- eosinophilic asthma
AE: headache, injection site rxn, oropharyngeal pain
COPD characteristics (3)
- main cause is smoking
- morning cough
- chronic cough with intermittent exacerbations
- upper resp infection, discharge can contain pus
IL-5 Inhibition - stop activation and prolif of eosinophils (name 2)
Mepolizumab
Reslizumab
COPD pathophysiology (3)
- fibrosis of small airways
- obstruction/destruction of alveoli and elastin fibers in lung parenchyma (emphysema) - shortness of breath
- chronic inflammation (bronchities) in small airways and lung parenchyma, not as well defined as in asthma
COPD treatment
non-pharm treatment (1)
what is not that effective?
- not a lot of drugs reverse it
1. stop smoking (fibrosis of small airways)
- glucocorticoids - transrepressor
- generally ineffective, but can try if asthma is also ther
- they interact with histone deacetylases (hDAC) which makes DNA no longer condensed and transcription factors cannot bind DNA
- smoking inhibits hDAC, so glucocorticoids aren’t effective - Bronchodilators
- doesn’t deal with underlying inflamm, useful palliation
- short acting: salbutamol, ipratropium
- long acting: salmeterol, formoterol
COPD treatment - Inhaled Anticholinergics
short-acting (1)
long-acting (1)
AE
- also used for asthma
Short-acting: ipratropium (derived from atropine)
Long-acing: tiotropium
AE: minimal, local rxns like dry mouth, nasal irritation, nose bleeds
COPD treatment - Inhaled Anticholinergics
MOA
- receptors (1)
- action (2)
- selectivity of tiotropium vs ipra
- parasymp stimulation of muscarinic receptors on bronchioles causes bronchoconstriction, induces bronchial secretions
need to block receptors! - mediated by M3 receptors (little M1)
- M3 also involved in mucus secretion, need to decrease it
- tiotropium has greater selectivity for M3, ipratropium is non-specified for M1-M3
COPD treatment - Roflumilast
MOA
- long-acting inhibitors of PDE4, increases cAMP
- reduce inflamm
- adjunct to bronchodilators for severe COPD
- orally
AE: GI symptoms, weight loss, naus, headache, insomnia
