Lecture 5: Asthma + COPD Flashcards
1
Q
Which drug(s) are B2 agonists?
A
Albuterol and Salmeterol
incr cAMP
2
Q
Which drug is a leukotriene antagonist?
A
Montelukast
“luk” for LEUKotriene antag, block glucotrienes
3
Q
Which drugs are muscarinic antagonists (2)?
A
Ipratropium, Tiotropium
blocks ACh
4
Q
Which drug(s) are inhaled corticosteroid?
A
Fluticasone
blocks cytokines
5
Q
Which drug(s) are monoclonoal anti-IGE antibodies?
A
Omalizumab
blocks abs
6
Q
Which drugs are used as a RESCUE for asthma ONlY (2)?
A
Ipratropium and Tiotropim
7
Q
Which drug is used as a RESCUE for BOTH asthma and COPD?
A
Albuterol
8
Q
Which drugs are used as a control for ASTHMA only (2)?
A
Montelukast, Omalizumab
9
Q
Which drugs are used as a control for COPD only (2)?
A
Ipratropium and Tiotropium
10
Q
Which drug(s) are used as control for BOTH asthma and copd?
A
Salmeterol, Fluticasone
11
Q
Incr in airway resistance is a hallmark of what type of lung disease?
A
Obstructive
12
Q
What are 2 characersistics of obstructive lung disease?
A
- Decr airflow (b/c decr elasticity or incr raw in zone 0-10)
- Limited airflow during EXPIRATION
13
Q
Low lung-cw compliance is a hallmark of what type of lung disease?
A
Restrictive
parenchyma fibrosis
14
Q
A pt with restrictive lung disease has
a.Low FEV1/FVC
b. High FEV1/FVC
c. Normal FEV/FVC
A
Normal FEV/FVC
equal decr in fev1 andfvc
15
Q
What is asthma
A
spasmodic contrctiion of smooth muscle in the bronchi
16
Q
What is COPD
A
- Bronchitis: inflammation of the bronchi and bronchioles (inr mucus)
- Emphysema: alveolar destruction
- Combination
also cystic fibrosis and bronchiectasis
17
Q
Which zone has higheset resistanace to airflow?
a. CZ
b. RZ
A
CZ (zone 1-10)
18
Q
Alveoli does not have ____
A
smooth muscle
19
Q
The further down we go in the airway towards the RZ the ____ the cross-sectional area
A
higher
lower resistance
20
Q
What are the factors that determine airway resistance?
A
- Structure of airways
- Airway smooth muscle contraction
- Lumen obstruction (mucus)
- Elasticity of Lung parenchyma
21
Q
For airway smooth muscle contraction, when receptors actiates, they will incr ____ by g protein ____ causing smooth muscle contraction
A
Intracellular Ca2+
G protein Q
22
Q
What are diff receptors that can lead to airway smooth muscle contraction when activated?
A
- Histamien
- Muscuranic
- LTD4
- Substance P
you can have histamine induced bronchospasm
23
Q
What does autonomic control of airway resisitance to the airways?
A
- Provides reflex arc for airway constriction following inhalation of irritants
- Provides airway dilation during exercise
24
Q
Explain the reflex arc for autonomic control of airway resistance
A
- You have an irritant come in
- Signal travels up to the medualla via afferent neurons
- Activates PNS and ACh is released
- Constriction of airway to remove irritant
25
Explain how autonomic control of airway resistance can dilate airways during exercise
* Decr PNS influence
* incr CIRCULATING epi (no direct SNS innervation of smooth airway muscle)
* Bronchodilation
26
Airway diameter depends on ____ of tisssue surrounding airways in lung parenchyma.
retractile force
## Footnote
as the lung expands, retractile force on airways incr
27
As the lung expands the what is pulling on the airway to keep it open, and if we loose this what can occur?
Alveoli, airway can collapse (emphysema)
28
Fxn of spirometry
used to acess lung parameters (airway resistance)
## Footnote
measures airflow
29
A pt with COPD (obstructive lung disease) has a high, low, or normal FEV1/FVC ratio?
Low, this is because with higher resitance it takes longer and it is harder for them to breathe out
## Footnote
men and taller ppl have higher FVC
FVC decr as you age from 45 on
30
Emphysema
a. major pathological changes
b. High or low resistance
c. high or low FEV1/FVC
a. airspace enlargemnent, destruction of alveoli
b. High resistance
c. Low FEV1/FVC
## Footnote
LOW eleastic recoil reduces structural support for bronchioles
31
Chronic Bronchitis
a. major pathological changes
b. High or low resistance
c. high or low FEV1/FVC
a. **mucus gland hyperplasia**, hypersecretion, bronchiole fibrosis
b. low resistance due to clogged bronchioles
c. low FEV1/FVC
32
Asthma
a. major pathological changes
b. High or low resistance
c. high or low FEV1/FVC
a. smooth muscle hyperplasia/spasmodic contraction, mucus inflammation, AHR
b. High resistance due to contracted bronchi
C. Low FEV1/FVC
33
Chronic disroder of the airfways that is complex and characterized by variable and recurring symptoms, airflow obstruction (bronchospasm). bronchial hyperresponsiveness, and underlying inflammation.
Asthma
## Footnote
lot of endotypes, we don't know why some ppl have mild or severe asthma
34
What is the "hallmark" of asthma?
Reversibility with bronchodilator.
35
True or false: Airway obstruction may be absent between attacks
True
## Footnote
pt is not constanly breathless, or having attacks
36
Explain the concept of airway hyperactivity
For a given concentration of chemical that causes bronchospasm, they will have a much bigger bronchospams
37
Muscurininc agonist, will activate ____ receptor and cause constriction
M3
38
You can test the severity of asthma my measuring airway responsiveness using what?
Methacholine
39
How do we measure the severity of asthma/airway responsiveness using methacholine?
We look at the amount of methacholine given to drop FEV by 20%
## Footnote
incr dise until FEV dropped by 20%
40
How can you tell if someone has severe asthma using methacholine?
If 0.3 mg/ml of methacholine causes a drop of FEV by 20%
## Footnote
asthmatis react to low dose of methocholine
41
How is asthma linked to allergy?
1. Allergen sensitization
2. Allergen-induced mast cell activation
## Footnote
allergen sensitization: B cells produce IGE instead of IGG (antigen becomes an allergen
Allergen-induced mast cell activation: IGE binds to mast cells and basophills which has a receptor called FCeR1. They release their granules with infla,,atory agents
42
What is allergen sensitization?
B cells produce IGE instead of IGG
## Footnote
an antigen becomes an allerefen
43
Early reaction of asthma involves what?
smooth muscle
44
Late reaction of asthma involves what?
cell infiltration
## Footnote
1. Hisamine release and cytokine release
2. Histamine causes quick constriction, cytokine causes late cell infiltration
45
What occurs to the lungs with asthma?
it remodels you keep repairing it
46
What are some characteristics of a severe asthamtic lung?
1. epithelial damage
2. goblet cell hyperplasia
3. smooth muscle hypertrophy and hyperplasia
4. basement membrane thickening
5. collagen deposition
6. submucosal fibrosis
7. angiogenesis
8. mucus plug formation
47
What is the role of vagal afferent nerves in respiratory diseases?
Sensory nerves that are activated by inflammation, irritants and pollutants
## Footnote
sense irritant
48
What is the role of vagal efferent nerves in respiratory diseases?
They are PNS nerves (cholinergic) innervating smooth muscle and mucosal glands
49
Activation of sensory nerves causes what 4 CNS reflexes?
1. Cough
2. Dyspnea
3. Bronchospasm (PNS)
4. Hypersecretion (PNS)
## Footnote
asthamtic subkects are hyperreflexive to inhaled irritants
50
COPD is linked to what?
Smoking
51
What occurs to your lung function when you smoke and why?
you have a decr in lung fxn bc you Decr your FEV1 at a faster rate than normal and there is **limited reversibility**
## Footnote
limited reversibility: a bronchodilator will not change FEV1
52
If you stop smoking at the age of 45, what occurs to your FEV1?
It can somewhat return to normal
53
If you stop smoking at the age of 65, what occurs to your FEV1?
It incr slightly, but not much
54
lWhat are the presenting symptoms associated with a pt who smokes and now has copd?
* cough, dyspnea
* lower lung fxn (lower airflow and hyperinflation)
* worse with exercise (6-min walk test)
* Exacerbation (infections)
* Airway hyperractivity (limited)
## Footnote
lungs have a higher RV
55
Pts with COPD tend to die from what?
bacterial infection
56
What role does neutrophils play in COPD?
They come in to get rid of damaged tissue but in the process, they damage normal cells in the lugns
## Footnote
neutrophilia: neutrophil elastase, matric mellatoproteinases, ROS-> leads to tissue destruction
57
As a result of neutrophils being released, what damages can occur?
* remodeling
* smooth muscle metaplasia
* fibrosis
* cell death
* higher resistance and lower elastic recoil leading to decr in airflow
* lower gas exchange
58
2 COPD subtypes
chronic bronchitis and emphysema
59
Chronic bronchitis is blue bloater or pink puffer? and why?
Blue Bloater
because lack of ventilation: Hypoxia (blue), edema (bloater)
60
What clinical manifestations do you see with chronic bronchitis and how does this affect resistance and airflow?
Excessive mucus production and fibrosis of bronchioles. You see incr in resistance and decr in airflow
## Footnote
mucus stuck in conducting airway so no O2 delivery
61
Chronic bronchitis is blue bloater or pink puffer? and why?
Pink puffer because lack of perfusion (mild hypoxia-pink) and bronchiole collapse (hard to breath-puffer)
62
What clinical manifestations do you see with emphysema and how does this affect resistance and airflow?
parenchymal/alv damage this incr resistance and decr airflow
## Footnote
lower alveolar structure, lower elastic recoil, lower structural support
63
Asthma summary table
1. age of onset
2. smoking history
3. atopy (allergy)
4. drop on FEV1
5. incr resistance reversible with B2 agonist:?
6. Hyperactivity
7. Family history
8. cough
9. cell infiltration
10. immunological paradigm
1. age of onset: usually < 40 (CHILDREN)
2. smoking history: not required
3. atopy (allergy): common (IgE)
4. drop on FEV1: episodic
5. incr resistance reversible with B2 agonist?: YES
6. Hyperactivity: very high
7. Family history: frequent
8. cough: yes (dry)
9. cell infiltration: **eosinophils**, mast cells, basophils
10. immunological paradigm: CD4+ Th2 cells, B cells
64
COPD summary table
1. age of onset
2. smoking history
3. atopy (allergy)
4. drop on FEV1
5. incr resistance reversible with B2 agonist:?
6. Hyperactivity
7. Family history
8. cough
9. cell infiltration
10. immunological paradigm
1. age of onset: usually > 40
2. smoking history:> 10 pack-years
3. atopy (allergy): no correlation
4. drop on FEV1: chronic
5. incr resistance reversible with B2 agonist?: Minimal
6. Hyperactivity: high
7. Family history:uncomoon
8. cough: yes (wet)
9. cell infiltration: **neutrophils**, macrophages
10. immunological paradigm: CD8+ Thcyt cells
65
What disease?
a. Gap is filled with mucus
b. Gap closes with bronchonstriction
c. Loss of strutural support, bronchi collapse
a. bronchitis
b. asthma
c. emphysema
## Footnote
all incr resistance
66
What are 4 ways drugs can incr airflow/decr resistance for obstructive diseases?
1. Actively cause bronchodliation (B-adrenoreceptor agonist)
2. Inhibit specific inflammatory mediators (leukotriene and muscarininc antagonits)
3. reduce inflammation (corticosteroids)
4. prevent inflammation (anti-IgE antibodies-for asthma only)
## Footnote
1. albuterol, salmeterol
2. montelukast, ipratropium, tiotropium
3. fluticasone
4. omalizumab
67
MOA for B2 adrenoceptor agonists
* Activation of b2 adrenorecptors on bronchial smooth muslce, incr cAMP ->relaxation->bronchodilation
## Footnote
1. facilitates sequestration of Ca2+
2. inacticates MLCK
3. Inactivates MLC20
68
Therapuetic uses for B adrenoceptor agonists
* Short acting (albuterol): rescule for asthma and COPD
* Long acting (LABA e.g. salmeterol): control for asthma and copd
## Footnote
salmeterol=everyday use
69
What do you give if you have an asthama attack?
Albuterol
70
Side effect of B adrenoceptor agonists is tachycardia, why?
B/c B2 also in heart and these drugs are not completely B1 inactive
71
Does albuterol and salmeterol work the same way?
Yes, its just that albuterol works more quickly than salmeterol
72
Asthama has a ____ increase in FEV1 while COPD has a very ____ increase in FEV1
robust, mild
## Footnote
complete reversal to 100% predicted with Asthma
73
Cysteinyl leukotrienes (LTC4, LTD4, LTE4) are known as the slow reacting substances of anaphylaxis, where can de novo synthesis occur?
Occurs in mast cells and basophils following allergen binding IgE and also in eosinophils and neutrophils.
## Footnote
LTC4 easilt converted into LTD4 then slowly in LTE4
74
Drugs can block cysteinyl leukotriences by what?
Being a 5-lipoxygenase inhibitor or being a cyst, T receptor antagonist
## Footnote
5-lipoxygenase causes the cascade leading to LTs being made
Cyst T receptor antags block receptor that leukotrienes are binding to, blocking signal cascade
75
Which has the highest concentration?
a.LTC4
b.LTD4
c. LTE4
LTD4
76
What does LTD4 bind to?
GPCR CysLT1 and CysLT2
77
CysLT1 and CysLT2 are G ____ coupled and activation leads to what
Gq coupled leadinng to
1. PLP C activation
2. IP3 and Dag production
3. Incr Ca2+ and PKC
4. Bronchospasm
## Footnote
all cysteinyl leukotrienea re effective at both receptors
78
Expression of bronchial smooth muscle (CysLT1) causes what?
Contractinn-> bronchospasm-> incr hyperplasia
## Footnote
also immune cells and mucus cells (incr inflammation)
79
Expression of bronchial smooth muscle (CysLT1) causes what?
Contractinn-> bronchospasm-> incr hyperplasia
## Footnote
also immune cells and mucus cells (incr inflammation)
80
Leukotriene antagonist
Montelukast
## Footnote
given orallu
81
MOA for Montelukast?
* CysLT1 antagonist
* Prevents CysLT1-induced bronchospasm, decr immune cell infiltration, no decr in AHR, very mild reveral of remodeling
82
Therapuetic use for Montelukast?
Control for asthma
## Footnote
NOT used for COPD b/c its not a TH2 disease
TH2 leads to production of IGE
83
reflec bronchospasm and hypersecretion via cholinergic activation of ____ receptors
M3
84
Nonselective muscurinic antagonist
Ipratropium bromide
## Footnote
given : inhalation
quartenery amine derivatice of atropine-charged-stays in lung when inhaled
85
What does tiotropium bromide inhibit?
M1, M3, but NOT M2
| does not binds to M2
## Footnote
given: inhalation
86
MOA for Ipratropium bromide and tiotropium bromide
| muscuranic antag
Blocks ACh induced acttivation of muscurinic receptors on
1. Airway smooth muscle (M3)-decr bronchospasm
2. Epithelial mucosal glands (goblet cells) (M3)- decr mucous secretion
87
Therapuetic use for Ipratropium bromide and tiotropium bromide
Rescue for asthma
control for COPD
88
Inhaled corticosteroids
Budesomide, **Fluticasone**
## Footnote
given: nasal or inhalation
analogs of corticosterone, steroid hormone (adrenal cortex)
89
MOA for **Fluticasone**
Steroid molecule **binds to cytoplasmic gluticorticoid receptor (GR),** dimerizes, enters nucleus, binds to DNA at specific sites leading to
DECR in pro-inflammatory protein production and
INCR in anti-inflammatory protein production
90
Modulation of protein expression of corticosteroids are slow-onset or fast onset and why?
Slow onset (more than 12 hours) because it alters the transcription of both pro and anti inflam
## Footnote
slow onset= not a rescue drug
91
Corticosteroid (fluticasone) ____ de novo transcription of PRO-inflam proteins ___
decr
IL4 and IL5
## Footnote
KNOW THIS
92
Corticosteroid (fluticasone) ____ transcription of ____ a potent ANTI-inflam protein that inhibits ____
INCR
IkB
NFkB
## Footnote
KNOW THIS
93
Steroids ____ IgE production from B cells and ____ mast cell degranulation
decr
inhibit
## Footnote
far less immune cell infiltratiom
pretty much eradicates late response
94
For asthma, what do steroids decr?
* Decr airway eosinophilia
* decr IgE production from B cells and inhibit Mast cell degranulation
## Footnote
decr Immune system
95
How does Corticosteroids affect COPD?
* have little effect on neutrophilia
* have no effect on mortality (will still die)
96
Corticosteroid side effects are due to what?
1. GR signaling (glucocorticoid/cortisol)
2. MR signaling (mineralcorticoid/aldisterone)
3. Both in multiple tissues
97
What are the side effects of corticosteroids if inhaled?
Incr risk of inf (oropharyngeal candiasis)
COPD: bacterial lung infections
## Footnote
incr risk for inf bec decr immune system
98
What are the side effects of corticosteroids if taken orally?
1. Hyperglycemia
2. Dyslipidemia
3. Hypertension
4. Osteoporosis
5. Cataracts
6. Glaucoma
7. Teratogenic
99
Anti-IgE antibodies
Omalizumab
## Footnote
given: subcutenous inj
monoclonal antibody IgG
100
MOA for Omalizumab anti-IgE antibody
binds to free IgE (Fc region), promoted destruction
* decr IgE from binding ro FCeR1 and FCeR2
* decr expression of FCeR1 on mast cells/basophils
* decr allergen-induced IgE crosslinling on mast cells/basophils
## Footnote
basically, we get rid of the reserves AKA circulating IgE and there is protein turnover which takes a few weeks. This means that the FceR gets lonely bc no more ige is coming over so it gets destroyed
101
MOA for Omalizumab anti-IgE antibody leads to what effects?
* prevents allergen-induced bronchospas,
* decr immune cell infiltration
* decr exacerbations
* no defect on AHR
* effect on remodeling unclear
102
Therapeutic use for Omalizumab anti-IgE antibody
control for severe steroid resistant asthma
103
Rate of onset for Omalizumab anti-IgE antibody
Circulating IgE destroyed in hours/days
Takes more than a weel for mast cell attached IgE to reduce
