Exam 3 Pathophysiology and Risk Factors of Asthma, COPD, and CF

Question 1

Antigen binding to IgE, triggering release of histamine, tryptase, LTC4, LTD4, and prostaglandins from mast cells and bronchial smooth muscle contraction is characteristic of which phase of asthma?

Answer 1

The early reaction in response to exposure to an antigen.

Question 2

Sustained bronchoconstriction, activation of TH2 lymphocytes (release of GM-CSF, IL4, IL5 and IL13), mucus hyper secretion, and eosinophil infiltration are characteristic of what phase of asthma?

Answer 2

Delayed reaction (or late phase) in response to antigen exposure.

Question 3

What factor is responsible for hyper responsiveness in an asthma exacerbation?

Answer 3

PAF – platelet activating factor

Question 4

What does ECP (something released by eosinophils) do?

Answer 4

Eosinophil cationic protein – cytotoxic and marker of inflammation

Question 5

What two factors cause goblet cell hyperplasia? What one factor helps maintain hyperplasia?

Answer 5

EGFR and CLCA help develop; Bcl-2 maintains

Question 6

What genetic polymorphism makes african americans more susceptible to asthma?

Answer 6

R576 polymorphism in the IL-4a receptor – enhances response to IL13 (hyper reactivity to inhaled antigens)

Question 7

Name three chronic changes that happen to airway tissue in asthma

Answer 7

Goblet cell hyperplasia/hypersecretion, basement membrane thickening, and smooth muscle hypertrophy

Question 8

Is COPD or asthma more associated with allergic response? Which onset comes later in life?

Answer 8

Asthma is allergic; COPD is later in life

Question 9

Which disease state can be associated with fibrosis of small airways, alveolar destruction, mucus hyper secretion, and hyperinflation of the lungs?

Answer 9

COPD

Question 10

The genetic deficiency of what anti protease can predispose someone to COPD?

Answer 10

a1-anti-trypsin

Question 11

Which disease is associated with TH1 and cytotoxic T cells?

Answer 11

COPD

Question 12

What transporter is somehow autosomal recessively defective in cystic fibrosis?

Answer 12

CFTR

Question 13

What does CFTR deficiency do to the body?

Answer 13

Leads to extremely viscous mucus that obstructs airflow, harbors pathogens, and obstructs the pancreatic duct. It also causes sweat to be extremely salty.

Question 14

What kind of channel is CFTR?

Answer 14

1480 aa protein ABC transporter of Cl- that is gated by PKA phosphorylation

Question 15

How does CFTR deficiency cause excessively thick mucus?

Answer 15

When functioning normally, CFTR inhibits ENaC-mediated Na influx that pulls water into the cells in the airway by pumping out Cl-, making it necessary for Na+ to stay outside in the mucus. When CFTR is defective, more sodium is drawn in so more water is drawn in, dehydrating the airway surface liquid and thickening the mucus.

Question 16

What second messenger concentration is increased after administration of a beta two agonist?

Answer 16

cAMP

Question 17

The increased cAMP level after beta agonist administration cause what effect within bronchiole smooth muscle?

Answer 17

Activation of PKA, which phosphorylates myosin LC kinase to its inactive form which will then not activate myosin LC. This leads to relaxation.

Question 18

What second messenger concentrations are increased after histamine/LTC4/LTD4 are released?

Answer 18

IP3 and calcium

Question 19

How do increased IP3 and calcium cause contraction?

Answer 19

They cause myosin LC kinase to phosphorylate myosin LC to its active form, which binds actin and causes contraction.

Question 20

How do glucocorticoids mitigate asthma?

Answer 20

Inhibit prostaglandin and leukotriene synthesis – decrease the hyperresponsiveness of bronchial smooth muscle

Question 21

How does theophylline work?

Answer 21

It inhibits PDE 4 (which usually breaks down cAMP so it increases cAMP) and antagonizes adenosine, decreasing IP3 and calcium. Also anti-inflammatory actions at low dose.

Question 22

The therapeutic window for theophylline is 10-15 mcg/mL. You see adverse effects at 20 mcg/mL. What are these adverse effects?

Answer 22

N/V, nervousness, abdominal discomfort, cardiac arrhythmias, hypotension, CNS stimulation, seizures, CV arrest

Question 23

Aside from side effects, what else is undesired with theophylline?

Answer 23

Prolonged half life in CHF patients, aggravation of seizures, interactions with Mg, Al, same CYP drugs (like Zileutin).

Question 24

What can cause a mast cell to degranulate?

Answer 24

Antigen binding to IgE on surface and clustering them (causing calcium influx), thermal stress, mechanical stress, cytotoxic agents, high dose morphine

Question 25

Do mast cells produce IgE?

Answer 25

No – IgE must bind to FcER receptors to be attached to the cell.

Question 26

What drugs stabilize mast cells?

Answer 26

Cromolyn sodium (Intal) and Nedocromil sodium (Tilade). Must be inhaled b/c insoluble. Taken prophylactically.

Question 27

What drug inhibits mast cell degranulation by preventing IgE binding to mast cells?

Answer 27

Xolair (omalizumab) – antibody given via SC injection q 2-4 weeks. 96% reduction free IgE! ADE related to injection, increased infection incidence

Question 28

How does zileuton (Zyflo) decrease inflammation in asthma?

Answer 28

It inhibits 5-lipoxygenase thereby inhibiting synthesis of LTB4, LTC4 and LTD4. Good for prophylaxis and treatment of chronic asthma.

Question 29

What should you watch out for when giving zileuton?

Answer 29

Increased INR in patients taking warfarin, doubles blood levels of theophylline, HA, dyspepsia

Question 30

What two drugs affect the same pathway as zileuton but in different ways?

Answer 30

Zafirlukast (Accolate) and montelukast (Singulair) – both antagonize the CysLT-1 receptors for LTC4 and LTD4.

Question 31

What should you be aware of when giving zafirlukast or montelukast?

Answer 31

HA, nausea, diarrhea, do not take with meals, take at night.

Question 32

What two quaternary ammonium compounds are used in COPD to open the bronchioles?

Answer 32

Ipratropium (Atrovent) and tiotropium (Spiriva)

Question 33

What effect do ipratropium and tiotropium have on second messengers and kinases within the cell?

Answer 33

Both decrease IP3 and calcium, leading to less activation of myosin LC kinase, resulting in less active myosin LC so less can bind to actin.

Question 34

What ultra LABA is approved for COPD only?

Answer 34

Indacaterol (Arcapta)

Question 35

In COPD patients with a genetic a1-antritrypsin deficiency (R576), what is happening to their cells? How can we replace this protein?

Answer 35

Excessive proteolytic damage to lung tissue.

Replace from pooled human plasma IV once/week

Question 36

What disease is ivacaftor (Kalydeco) used in?

Answer 36

Cystic fibrosis – drug holds CFTR channel open

Question 37

What patients can receive ivacaftor (Kalydeco)?

Answer 37

Patients >6 yo with G55D/S mutation – ~1-2% of CF patients

Question 38

How is theophylline dosed?

Answer 38

3 mg/kg q 6-8 hours or 7 mg/kg q 12 hours

Question 39

What affect does smoking have on theophylline levels?

Answer 39

Decreases levels by up regulating metabolic enzymes. Rifampin, phenytoin, and phenobarbital do this too.

Question 40

Name potential asthma triggers

Answer 40

Respiratory infections, colds, cigarette smoke, allergens (pollen, mold, dander, food, etc.), exercise, cold air, fumes, emotions, co-morbid conditions (allergies/GERD), drugs (aspirin, beta blockers)

Question 41

Name four risk factors for developing asthma

Answer 41

African American race, asthmatic parents, allergies, exposure to fumes, gases, or dust

Question 42

During what phase are airway edema and hyper responsiveness present–early or late?

Answer 42

Late phase – cough at night?