Exam 2 - Asthma/COPD Flashcards
What is the pathogenesis of asthma, in terms of triggers and physiological response?
Two phases -
- Early reaction: As the antigen binds to IgE, the binding triggers a release of histamine, tryptase, leukotrienes, and prostaglandins from mast cells. This causes immediate bronchial smooth muscle contraction and vascular leakage.
- Delayed reaction (2-8 hours): Sustained bronchoconstriction, activation of TH2 lymphocytes (causes release of inflammatory mediators including granulocyte-macrophage colony-stimulating factor and IL-4,5,13. Goblet cells hypersecrete mucus. Lastly, eosinophils are reaching the cells.
What is the role of goblet cells in the pathogenesis of asthma?
Goblets hyper-secrete mucus during asthma.
In healthy cells, Goblet cells make up only 1/7th of the population (the rest are ciliated), but during hyperplasia, we lose the ciliated cells and get more goblet cells. This causes hyper-secretion of mucus and we aren’t able to transport the antigen away (due to loss of ciliated cells).
Cytokines from TH2 cells, bacterial, neutrophils, and oxidants can cause this hyperplasia. EGFR and CLCA are involved in the development of hyperplasia and Bcl-2 is involved in the maintenance of hyperplasia.
Why are β2-adrenergic agonists the drugs of choice for acute asthma attacks? What effects do these drugs have on the respiratory system of the asthmatic patient?
β2 agonists relax bronchial smooth muscle (bronchodilation), and that’s where the effected area is for asthma.
These activate Gs pathway and PKA converts myosin LC kinase -> MLCK-(PO4)2, which stimulates relaxation.
They also inhibit the release of mediators from mast cells, inhibit microvascular leakage, and increase microciliary transport of mucus.
Ex of SABAs: Albuterol (optimal β2 selectivity), Terbutaline (causes increased palpitations), and Levalbuterol (more expensive).
What are the effects of theophylline on the respiratory system and other systems? What is the relationship of these effects to the therapeutic use and adverse effects?
Theophylline is in tea. It can inhibit the binding of adenosine to A1R, which means the contraction pathway doesn’t start. It also inhibits PDE4, which helps to increase cAMP levels, promoting relaxation.
Theophylline has a very narrow therapeutic range. Some AEs include nausea, vomiting -> cardia arrhythmias, hypotension -> seizures cardiac arrest.
Also theophylline competes with other drugs, which can make it more toxic.
What is the rationale for the use of glucocorticoids in the treatment of asthma and the advantage of using inhaled doses over daily oral doses?
The goal of glucocorticoids is to alter the gene expression of proteins that are important in the inflammatory process. The point is the inhibit the synthesis of prostaglandins and leukotrienes. This will in turn decrease the hyperresponsiveness of bronchial smooth muscle cells that occurs in chronic asthma.
Use inhaled so that there are less systemic side effects?
What is the rationale for using Cromolyn in the treatment of asthma and how does this rationale compare with that of the β2-adrenergic agonists?
These are of value when taken prophylactically. It’s inhaled as a powder or aerosolized solution. These inhibit mast cell degranulation.
This is used as pretreatment for mild to moderate chronic asthma (mostly exercise induced). It blocks bronchoconstriction that is caused by antigen inhalation, exercise, aspirin, and environmental toxins.
What is the mechanism of action of omalizumab, and what’s the rationale for it’s therapeutic use?
Biologics - These usually block receptors or cytokines. It’s used when steps 1-5 don’t work.
Omalizumab is an anti-IgE produce that binds to IgE and therefore blocks the crosslinking of IgE (by antigen binding) on the mast cells. It is approved for Type 2 High Inflammation.
What are the differences between the mechanisms of action of the antileukotrienes?
5-Lipoxygenase oxygenation of arachidonate: Block this (FLAP enzyme) so that the production of leukotrienes can’t proceed.
- Zileuton (Zyflo) does this
Zafirlukast (Accolate) & Montelukast (Singulair) - Selective competitors (mimic) at CysLT-1 receptor, causing inhibition of late phase bronchoconstriction.
Why do Ipratropium and Tiotropium have some use in treating bronchoconstriction (what is the mechanism)?
LAMAs are used in COPD treatment. Ipratropium (Atrovent) and Tiotropium (Spiriva) are quaternary ammonium compounds that have limited systemic absorption and go straight to the lungs
Ipratropium - Inhibits the contraction pathway by inhibiting ACh binding to M3R.
What are the chemical structures of distinct classes of drugs used to treat asthma?
SABAs - t-butyl and alcohol phenyl ring.
LABAs - Has this central N with two long chains w/ aromatic rings attached.
Methylxanthines (Theophylline) - Xanthine ring structure
Cromolyn - Two cromolyn rings
LAMAs - quaternary amines.
What are some novel strategies for the treatment of asthma (+ justification)?
???? Seebri Neohaler - glycopyrrolate inhalation powder as stand-alone monotherapy for COPD. This can be used for long-term maintenance treatment of airflow obstruction in pts with COPD.
What is the emerging pathogenesis of e-Cigarettes and Vaping?
E-cigarettes have many toxins.
EVALI - exogenous pneumonitis-like reaction. Vitamin-E acetate was being used to solubilize THC, and it was found that this Vitamin E was leading to this inflammatory response in the lungs.
- Involves airway epithelial cells, alveolar macrophages, granulocytes/neutrophils.
- NETosis (process of recruiting lots of neutrophils, then they die and release their DNA) leads to greater increase of inflammation and other respiratory implications.
What is the pathogenesis of COPD and how does it compare to the pathogenesis of asthma?
Unlike asthma, COPD is not related to an allergic response. It’s more linked to pollutants (smoking). It’s irreversible (unlike asthma).
COPD remodeling: TH1 cells invovled (TH2 in asthma). Get alveolar wall destruction (emphysema), leaving a hollow alveoli, leading to irreversible damage causing shortness of breath.
Key differences between COPD and asthma - COPD has much more fibrosis. COPD involves TH1 and Tc1 cells, but asthma mainly involved Th2.
What is the pathogenesis of cystic fibrosis (CF) and how does it affect lung function?
Cystic fibrosis - Completely genetic. CF patients have obstructed lung airflow that leads to an increase in bacterial colonization (ex. pseudomonas). It also leads to obstruction of pancreatic duct in the gut, which interferes with digestion.
CFTR gene is affected. It encodes an ABC transporter that functions as a Cl- channel. CFTR is expressed in airway epithelium, sweat duct epithelium, and pancreatic duct epithelium.
In sweat - If the CFTR gene isn’t working and we therefore don’t have chloride function, we will have increased Cl- in the extracellular space (in mucus and sweat). This causes an additional increased Na+ because they are linked.
In lung - Loss of CFTR function inhibits the ENaC Na+ regulation. This leads to dehydration of lungs because water is trying to balance the influx of Na+ and Cl-.
What is the mechanism of action of drugs that are currently used to improve lung function in CF, as well as new, genotype-specific drugs that are under development?
Ivacaftor (Kalydeco) - This potentiates Cl- current through CFTR in response to cAMP. This helps rehydrate the lung.
Mucolytics - Enzymes that can break down mucus into a more liquid form to help hydrate the lungs.
Bronchodilators & Antibiotics are useful, too.
In development:
- Ataluren is used to suppress premature stop codons in order to make the full protein.
- VC-809 is a small molecule chaperone used to help protein folding.
- Bronchitol rehydrates mucus.
What makes LABAs “long acting”
These are more resistant to MAO and COMT, which allows them to last longer in the body. They also can be more lipophilic.
Ex of LABAs: Formoterol (resistant to MAO/COMT and has increased lipophilicity).
Whats the difference between type 2 low inflammation and type 2 high inflammation?
Type 2 Low Inflammation - Neutrophilic, involves IL6, IL8, and IL17. It’s harder to treat and more likely to have adverse events when treatments have been used.
Type 2 High Inflammation - Eosinophilic, involves IL4, IL5, and IL13. This involves PGD2 stimulation of the DP2 receptor.
What are the main pulmonary targets for asthma, COPD, and CF?
Asthma: Bronchodilation, anti-inflammation, inhibition of mast cell degranulation, inhibition of eosinophilia.
COPD: Bronchodilation (muscarinic and adrenergic receptor based) and protease inhibitor strategy
CF: Protein folding, mucus rehydration, bronchodilation & antibiotics.
What are the signs and symptoms of asthma?
Signs -
- Expiratory wheezing
- Dry hacking cough
- Allergies
- Low FEV1/FVC that goes up after β-agonist use
- High eosinophil count and blood IgE concentration
Symptoms -
- Episodic symptoms of airflow obstruction (chest tightness, dyspnea, non-productive cough)
- The airway obstruction is reversible
What are the intermittent asthma classifications? (frequency of symptoms, nighttime awakenings, SABA use, interference with normal activity, lung function, and exacerbations requiring oral steroids)
Frequency - ≤ 2 days/week
Nighttime awakenings - ≤ 2 times/month
SABA use - ≤2 days/week
Interference w normal activity - none
Lung function - FEV1 normal between exacerbations, FEV1 > 80% of predicted, FEV1/FVC normal
Exacerbations - 0 or 1/year
What are the mild persistent asthma classifications? frequency of symptoms, nighttime awakenings, SABA use, interference with normal activity, lung function, and exacerbations requiring oral steroids)
Frequency - > 2 days/week
Nighttime awakenings - 3-4 times/month
SABA use - > 2 days/week, but not daily and < 1 time/day
Interference w normal activity - minor
Lung function - FEV1 > 80% of predicted, FEV1/FVC normal
Exacerbations - ≥ 2/year
What are the moderate persistent asthma classifications? frequency of symptoms, nighttime awakenings, SABA use, interference with normal activity, lung function, and exacerbations requiring oral steroids)
Frequency - daily
Nighttime awakenings - > 1 time/week
SABA use - daily
Interference w normal activity - some limitation
Lung function - FEV1 > 60-80% of predicted, FEV1/FVC reduced 5%
Exacerbations - ≥2/year
What are the severe persistent asthma classifications? frequency of symptoms, nighttime awakenings, SABA use, interference with normal activity, lung function, and exacerbations requiring oral steroids)
Frequency - throughout the day
Nighttime awakenings - often 7 times/week
SABA use - several times a day
Interference w normal activity - extremely limited
Lung function - FEV1 > 60 of predicted, FEV1/FVC reduced 5%
Exacerbations - ≥2/year
What is an EIB?
EIB - Exercise induced bronchospasm
- Pt has history of cough, chest tightness, or endurance problems during exercise.
- Drop of FEV1 by > 15% of baseline
- Bronchial hyperresponsiveness
What is the treatment step outline for asthma pts under 5 years old? (4 steps)
- PRN SABA
- Low ICS
- Double low dose ICS
- Continue & refer to specialist
Alternative -
- LTRA or intermittent ICS
- Low ICS + LTRA
- increase ICS frequency, add LTRA or intermittent ICS if haven’t yet
What is the treatment step outline for asthma pts ages 6-11 years old? (5 steps)
- PRN SABA
- Low ICS
- low ICS-LABA or med. ICS
- med. ICS-LABA & refer for advice
- refer for phenotypic assessment +/- add on therapy like anti-IgE
Alternative -
- Take low ICS with SABA when taken or just low ICS
- LTRA or concomitant low ICS + SABA
- Low ICS + LTRA
- High ICS-LABA or add tiotropium or add LTRA
- Add anti-IL5 or add low OCS
What is the treatment step outline for asthma pts ages 12+? (6 steps)
- PRN SABA
- low ICS + PRN SABA or PRN concomitant ICS + SABA
- Daily and PRN combo of low ICS-formoterol
- Daily and PRN combo of med. ICS-formoterol
- Daily med/high ICS-LABA + LAMA and PRN SABA
- Daily high ICS-LABA + OCS + PRN SABA
Alternative -
- Daily LTRA and PRN SABA or Cromolyn/Nedocromil/Zileuton/Theophylline & PRN SABA
- Med. ICS + PRN SABA or low ICS-LABA (or ICS + LAMA or low ICS + LTRA) & PRN SABA or low ICS + theophylline or zileuton & PRN SABA
- med. ICS-LABA or med. ICS + LAMA & PRN SABA or med ICS + LTRA & PRN SABA
- med ICS-LABA or high ICS + LTRA & PRN SABA
What’s the difference between “difficult to treat” asthma and severe asthma?
Difficult to treat - Pt has symptoms/exacerbations despite being on appropriate GINA step 4 therapy or taking maintenance OCS.
Severe asthma - Difficult to treat pts who are still uncontrolled despite addressing factors that are contributing to symptoms (like inhaler technique, social issues, adherence, etc.) & high dose ICS therapy trials with 3-6 month assessment.
If a patient's labs while on high dose ICS or OCS are as follows, what is the likely asthma assessment: Blood eosinophils > 150 cells/uL FeNO > 20ppb Sputum eosinophils > 2% Allergen-driven asthma
Refractory Type-2 asthma
- Assess adherence and modifiable risk factors
- Treat for other phenotypes if indicated (AERD, ABPA)
- Consider costs/route/patient preference prior to initiating biologic agents
What are 4 characteristics of type 2 asthma?
- Seen in 50% of severe asthmatics
- Involves production of cytokines like IL-4, IL-5, IL-13 by the adaptive immune system in response to allergens
- Characterized by FeNO and eosinophils
- Usually responds to high dose ICS/OCS, but the patients can be refractory
What does a patient need to be eligible for anti-IgE therapy?
- During skin prick/IgE test: Sensitivity to inhaled allergens
- Pretreatment serum IgE: 30-700 IU/mL
- Pt weighs 66-330lbs (30-150kg)
- At least 1 severe exacerbation within the past year
What does a patient need to be eligible for anti-IL-5 therapy?
- Blood eosinophils >300 cells/uL
- At least 1 severe exacerbation within the past year
What does a patient need to be eligible for anti-IL-4 therapy?
At least 1 severe exacerbation within the past year AND At least of of the following: - Blood eosinophils > 300cells/uL - FeNO > 25 ppb -Pt requires maintenance OCS
After biologics therapy for asthma, what do we do if we had good results vs. if we had bad results?
Good: Re-evaluate every 3-6 months, consider tapering use of OCS or reduction of ICS dose, don’t trial withdrawal biologic within 12 months
Bad: Review the basics like adherence, technique, risk factors, investigate other things like a chest CT/induced sputum, maybe add low OCS/Macrolides with help by specialist.
What’s the goal of therapy of severe acute asthma?
- To rapidly reverse the airway obstruction and inflammation
- To correct the hypoxemia (Goal oxygen saturation is 93-95% in pts older than 11, 94-98% is pts 11 and under)
- To prevent complications like a pneumothorax or respiratory arrest/intubation
What’s the first line management of severe acute asthma?
- Systemic corticosteroids (oral or IV): 1-2 mg/kg/day; Prednisone/Prednisolone/Methylpredisolone; Max dose is based on age.
- Inhaled albuterol +/- ipratropium if pt is in ED (not if hospitalized)
- Supportive care: Oxygen supplementation/fluid resuscitation
- If pt is having anaphylaxis/angioedema: Epinephrine IM injection
What is the second line management of severe acute asthma?
- Continue appropriate systemic corticosteroids
- Transition from continuous SABA to PRN (monitor HR and K+)
- Magnesium sulfate (IV or inhaled): Slow IV infusion (40-50mg/kg) is most common, also can inhale.
What are some things we may see as third/fourth/rescue treatment for severe acute asthma?
Terbutaline Aminophyllin/theophylline LTRAs Heliox Antibiotics Sedatives
Therapies will vary based on patient and institution. There’s not much data supporting exactly what to do.
What is the process of the synthesis and metabolism of histamine?
Synthesis: Histidine is decarboxylated to histamine. This reaction is catalyzed by L-histidine decarboxylase. This occurs in mast cells and basophils and is stored in granules for rapid release in response to antigens and cell lysis.
Metabolism: Histidine can be metabolized into N-methylhistamine or Imidazole acetic acid, both of which are inactive. Those can be later metabolized into N-methylmidazole acetic acid and imidazole acetic acid riboside, which are also inactive.
What is the mechanism by which histamine is stored and released?
There are storage granules in which histamine is complexed with sulfated-polysaccharides, heparin sulfate, chondroitin sulfate, and proteases. All of this is released during mast cell degranulation.
There’s also histamine in the some areas of the brain and some in the fundus of the stomach, utilized for stimulation of acid secretion.
Release of histamine:
- Antigen mediated binding of the antigen to antibodies that are bounds to the cell surface causes granules to be released.
- Thermal or mechanical stress, cytotoxic agents like venom, and various drugs like high dose morphine also cause granule release.
IgE bind to FcϵR -> antigen bind to IgE -> FcϵR cluster -> influx of Ca2+ via CRAC -> granules released
How can we differentiate between the effects of histamine due to stimulation of H1 receptors and H2 receptors?
H1 receptor - These are in the CV system, respiratory system, and GI smooth muscle. Through the phosphoinositol pathway, the activation of these receptors causes smooth muscle contraction. Also, H1 receptor is linked to vasodilation and stimulation of sensory nerves, leading to sneezing and itching.
H2 receptor - In CV system, GI smooth muscle, and stomach. This receptor is linked to relaxation of vascular smooth muscle and gastric secretion.
What are the effects of histamine on the respiratory and cardiovascular systems?
Respiratory - Constriction of bronchial smooth muscle that is mediated by H1.
Cardiovascular - Moderate increase in rate and force of contraction of the heart due to H2 receptor & vasodilation due to H1 in endothelium and H2 in smooth muscle.
