Asthma Flashcards
1
Q
What is asthma?
A
Episodic bronchospasm resulting from an exaggerated bronchoconstrictor response to various stimuli
2
Q
What stimuli causes bronchospasm?
A
- Bronchial hyperreactivity
- Chronic bronchial inflammation
3
Q
What does episodic bronchospasm cause?
A
dyspnea, cough, and wheezing
Dyspnea- difficulty breathing or SOB
4
Q
Does asthma affect children or adults more? What are the incidence rates
A
A: Children
- Adults: ~5%
- Children: 7-10%
5
Q
How many fatal cases of asthma are there per year?
A
- 3000 fatality cases per year in US
6
Q
What is characteristic of asthmatic airways?
A
The smooth muscle walls of asthmatic airways are inflamed, thickened, and tightened. The air is trapped in the alveoli.
7
Q
What are the hallmarks of asthma?
A
- Wheezing, coughing, shortness of breath
- Narrowing of airways
- Inflammation and airway hyperreactivity
- Release of inflammatory mediators
Oscillating pressure effect –> wheezing
8
Q
T of F: Asthma is a heterogenous disease triggered by limited inciting agents.
A
False
* Asthma is heterogenous, but it is triggered by a VARIETY of inciting agents
9
Q
What are the types of asthma?
A
- Extrinsic asthma (allergic asthma or classical asthma)
- Instinsic asthma
10
Q
Describe extrinsic asthma.
A
- A hypersensitivity reaction induced by exposure to extrinsic antigen, such as dust, mite, molds, or pollens
- Commonly associated with other allergy in the pt as well as in other family members
- EARLY onset in life
- Characterized by high serum IgE levels and eosinophil count
- Driven by Th2 subset of CD4+ T cells
11
Q
Describe intrinsic asthma.
A
- Nonimmune triggering mechanism
- Triggered by things like: aspirin, viral infection, cold, psychological stress, and exercise
- No personal or family history of allergy
- Serum IgE levels are within normal range
12
Q
What are the triad of lung disease inducers?
A
- Genetic
- Environmental
- Medications
13
Q
What is IAR?
A
Immediate asthmatic response
14
Q
What is LAR?
A
Late asthmatic response
15
Q
What is FEVI?
A
- Forced Expiratory Volume
16
Q
What is ECP?
A
eosinophil cationic protein
* cytotoxic secretory protein & marker of inflammation
17
Q
What is PAF?
A
Platelet activating factor
* hyper-responsiveness
18
Q
What do neutrophil proteases do?
A
- May activate eosinophils
19
Q
What is a periostin?
A
matrix protein that is used as an asthma biomarker
20
Q
IgE is bound to_____.
A
Mast cells
21
Q
Crosslinking by the antigen leads to____
A
Crosslinking by the antigen leads to degranulation of the mast cells and basophils, releasing histamine, cytokines, and other inflammatory mediators.
22
Q
What type of asthma response is acute bronchoconstriction?
A
Immediate Asthmatic Response
* IAR
* The immediate asthmatic response (IAR) happens after you’ve been exposed to an allergen and sensitized (meaning your body produces IgE in response to it).
23
Q
Describe the process of sensitization.
A
IAR occurs after sensitization.
* Mediated by IgE, produced in response to exposure to foreign proteins
* IgE binds to FceR-1 on mast cells in the airway mucosa.
24
Q
How does re-exposure work?
A
When you encounter the allergen again, it triggers these IgE antibodies on the mast cells to release histamine, tryptase, leukotrienes (LTC4, LTD4), and prostaglandin D2 (PGD2).
* re-exposure triggers the release of mediators from the mast cells during mast cell degranulation.
25
What mediators do mast cells release?
histamine, tryptase, leukotrienes (LTC4 and LTD4) and prostaglandin D2 (PGD2)
26
What do the mediators do to the smooth muscle?
The mediators released after the trigger cause the smooth muscle to contract and vascular leakage.
27
What directly causes reflex bronchoconstriction?
Direct stimulation of subepithelial vagal (parasympathetic) receptors provokes reflex bronchoconstriction.
28
How type of response is sustained bronchoconstriction?
Late asthmatic response (LAR)
29
When does the LAR occur after the early asthmatic response?
3-6 hours
30
What are steps of the late asthmatic response?
Activation of TH2 Cells: After the early response, immune cells called T-helper 2 (TH2) cells become activated. These cells release certain chemicals called cytokines (like IL-5, IL-9, and IL-13).
* Recruitment of Eosinophils: The cytokines attract eosinophils (a type of white blood cell) to the site of inflammation.
* Mucus Production & IgE: The cytokines also stimulate mucus production from bronchial epithelial cells, which can further block the airways.
* They promote IgE production by B cells, contributing to the ongoing allergic response.
Eosinophil Activation: The eosinophils release toxic proteins like major basic protein (MBP), eosinophil cationic protein (ECP), and peroxidase, which cause tissue damage.
* Sustained Inflammation: This whole process amplifies and prolongs the inflammation, even without needing further exposure to the original allergen.
31
Describe the airway remodeling in asthma.
Epithelium
* Hyperplasia
* Hypersecretion
Basement membrane
* Thickening
Smooth muscle
* Hypertrophy
32
How did the NIH guidelines on asthma change in 1991?
Started to recognize asthma as a chronic inflammatory disease and recommended corticosteroid therapy
33
How did the NIH guidelines on asthma change in 2007?
National Asthma Education and Prevention Program (NAEPP) guidelines formed
34
How did the NIH guidelines on asthma change in 2020? (long lag)
NHLBI – NAEPP – latest update
* Grade Process is new, but one size does not fit all
* Important exception to the update was biologics!
35
What is GINA?
Global perspective that is updated more frequently – reviews literature in the last year. However, it is not officially a guideline.
36
What were the 6 topic areas that were updated in the 2020 guidelines?
1. Use inhaled corticosteroids when needed for recurrent wheezing or persistent asthma
2. Use long-acting antimuscarinic agents (LAMAs) with inhaled corticosteroids for long-term asthma management.
3. Use one or more methods to reduce exposure to indoor asthma triggers
4. Immunotherapies: eg. allergy shots
5. Consider using fractional exhaled NO to manage asthma or confirm diagnosis
6. Consider bronchial thermoplasty (BT) to treat persistent asthma
37
What are the 6 phases of pharmacological management of asthma?
1. SABA prn
2. Low-dose ICS and prn SABA (or prn ICS and SABA)
3. Daily and prn combination low-dose ICS-fomoterol (or several combinations of ICS and SABA doses)
4. Daily and prn combination medium dose ICS-fomoterol (or inceased doses of ICS, ICS-LABA combinations, theophylline, or ICS-Zileuton)
5. Daily medium-high dose ICS-LABA + LAMA and prn SABA (or med-high dose ICS-LABA of ICS+ LTRA, and prn SABA)
6. Daily high dose ICS-LABA or oral systemic corticosteroids + prn SABA
## Footnote
Steps 4-6: Consider adding biologics- anti-IgE, anti-interleukins
38
What are sympathomimetics?
* Bronchodilators
* "Relievers"
39
What are inhaled corticosteroids (ICSs)?
* Anti-inflammatory steroids
* "controllers"
40
What are the most common pharmacological treatments in asthma (two classes)?
1. Sympathomimetics
2. Inhaled Corticosteroids
41
What are leukotriene pathway inhibitors?
* 5-lipoxygenase inhibitors
* LTD4 antagonists
42
What are other less common pharmacological treatments for asthma?
* Methylxanthine drugs
* Antimuscarinic agents
* Cromolyn and nedocromil
* Monoclonal antibodies
43
What is the mechanism of action for sympathomimetics?
* Binds to B2 adrenergic receptors in the bronchial smooth muscle
* Increases cAMP conc., which relaxes the smooth muscle.
44
What is an example of a nonselective sympathomimetic drug?
Epinephrine
* IV injection to relieve a severe attack
45
What is an example of a Beta-selective sympathomimetic drug?
Isoproterenol (displaced by B2 selective drugs)
46
What is a clinical consideration with Beta-selective sympathomimetic drugs?
Beta-selective sympathomimetic drugs also affect the heart, which has B1 adrenergic receptors.
47
What are some drugs classified as B2 selective sympathomimetic?
Short-acting and long-acting B2 agonists
48
What sympathomimetic drug type is MOST used for the tx of asthma?
B2 selective
49
What is used to prevent/treat bronchial smooth muscle constriction?
B2-adrenergic receptor agonists
50
What happens when the B2-adrenergic receptors are activated by cytoplasmic G proteins?
Stimulation of β2-adrenergic receptor activates cytoplasmic G proteins, which in turn activate adenylyl cyclase to produce cyclic adenosine monophosphate (cAMP), generally thought to be responsible for the bulk of activity through activation of various proteins by cAMP-dependent protein kinase A (PKA)
RESULT: This activation, in turn, decreases unbound intracellular calcium, producing smooth muscle relaxation, mast cell membrane stabilization, and skeletal muscle stimulation.
50
What is the importance of the stimulatory G protein of adenylyl cyclase of Beta-adrenergic receptors?
* This enzyme produces the second messenger cyclic adenosine monophosphate (cAMP).
* SUMMARY: In the lung, cAMP decreases calcium concentrations within cells and activates protein kinase A.
* MOA: Both of these changes inactivate myosin light chain kinase and activate myosin light chain phosphatase. In addition, beta-2 agonists open large conductance calcium-activated potassium channels and thereby tend to hyperpolarize airway smooth muscle cells.
* RESULT: The combination of decreased intracellular calcium, increased membrane potassium conductance, and decreased myosin light chain kinase activity leads to **smooth muscle relaxation** and **bronchodilation**.
51
Describe the structure activity relationship for B2 selective agonists.
Bulky N-substitutions
* B2 selective
Substitutions in the phenyl ring (resocinol, salicyl alcohol)
* B2 selective
* COMT resistant (prolonged bronchodilation)
Overall: Mostly racemic mixture (ex. levalbuterol). HW, only R-isomer is active.
52
What toxicities could occur with B2 selective agonists?
* Tachycardia, arrhythmias- less of a concern for B2 selective agonists
* Skeletal muscle tremors
* Induction of tachyphylaxis- reduction in the bronchodilator response upon regular uses.
53
List out the most common short-acting B2 agonists (SABA).
Albuterol, terbutaline, metaproteroenol, levalbuterol, and pirbuterol
54
When do we use SABAs?
PRN for acute attacks
55
List out the common long-acting B2 agonists (LABAs).
Salmeterol, fomoterol
56
What are the uses of LABAs?
* Additional therapy for pts who are currently using inaled glucocorticoids
* Not for acute attacks but for daily regular use.
* No anti-inflammatory action; should not be used as monotherapy for asthma (black box warning)
57
What are the commonly available combo inhalers w/ corticosteroids?
* Fluticasone propionate/salmeterol (Advair®)
* Budesonide/formoterol (Symbicort®)
* Mometasone furoate/formoterol (Durela®)
57
What are the characteristics of metaproterenol (Alupent)?
* Resorcinol analogue of isoproterenol
* Somewhat selective for β2 receptor
* Least potent β2 agonist
* 5-min onset and 4-hr duration when inhaled
* Good oral bioavailability
| SABA
58
What are the characteristics of terbutaline (Brethine)?
* N-t-butyl analogue of metaproterenol
* Greater B2 selectivity
* 3-fold greater potency than metaproterenol at B2 receptors
* Good oral bioavailability
* ADVERSE EFFECT: greater incidencce of palpitations
| SABA
59
What are the characteristics of Albuterol (Ventolin)?
* Most widely used
* Salicyl alcohol in the phenyl ring--> resistant to COMT
* optimal B2-selectivity
* 5-min onset and 4-8 hr duration of action when inhaled.
* N-t-butyl and salicyl alcohol phenyl ring, which gives it optimal B2-selectivity
Levalbuterol (Xopenex®) is R-isomer.
* Greater potency, but more expensive
* Used when Albuterol has side effects in pediatric patients
| SABA
60
What are the characteristics of Pirbuterol (Maxair)?
* Analogous to albuterol except the pyridine ring.
* Comparable duration of action as albuterol
* Less potent than albuterol
61
What are the key characteristics of salmeterol?
* Greater water solubility and moderate lipophilcity
* 20-min onset and 12-hr duration of action
* Moderate resistance to MAO/COMT
* Available as a powder
* Structure: an N-phenylbutoxyhexyl substituent in combination with a β-hydroxyl group and a salicyl phenyl ring for optimal direct-acting β2-receptor selectivity and potency.
* Salmeterol has the greatest receptor affinity of all the adrenergic agonists.
* A controller for the long-term treatment of asthma and is not recommended for quick relief of an acute attack.
* It also is available in combination with the steroid fluticasone propionate (Advair Diskus).
* There was a small but significant increase in asthma- related deaths among patients receiving salmeterol during a large clinical trial, and as a result, the FDA has recommended that it not be used as monotherapy for asthma in either children or adults.
* Subgroup analyses suggested that the risk may be greater in black patients compared with Caucasian patients
62
What is characteristic of Formoterol?
* Highest receptor affinity
* Rapid onset than with a comparable duration of action to Salmeterol
* Increased lipophilicity- increased resistance to COMT/MAO
* Arformoterol (Brovana) is the (R,R)-enantiomer
* Structure: Formoterol has a β-directing N-isopropyl-p-methoxyphenyl group and a unique m-formamide and p- hydroxyphenyl ring, which provides selectivity for β2-receptors.
* Long-acting agonist
* The most prominent metabolic pathway involves direct glucuronidation at the phenolic hydroxyl group ([31]). O-Demethylation followed by conjugation at the phenolic 2′-hydroxyl group also occurs and appears to involve four cytochrome P450 isozymes (CYP2D6, CYP2C19, CYP2C9, and CYP2A6).
* Fomoterol has a more rapid onset as compared to salmeterol while maintaining the same long duration of action.
63
What form are LABAs available?
Powders
64
Should LABAs be taken as a monotherapy?
NO- FDA warning
66
What route of administration is the best choice for acute attacks?
* Inhalation
* PRN for acute or anticipated attack
* Provides for local action on bronchial smooth muscle
* Pts should not use albuterol more than 2x/week except for EIA.
67
What are the adverse effects of B2-agonists?
Skeletal muscle tremors
Tachycardia and palpitations.
* Occurs less with 2 selective agents.
* High doses of β2 selective agents may stimulate β1 receptors in the heart.
* Reflex tachycardia due to vasodilation caused by activation of β2 receptors.
| Vasodilation--> decreased BP--> increased HR
68
What are inhaled corticosteroids (ICSs)?
Maintenance therapy for persistent asthma
Not curative
* “controller”
* Effective only so long as they are taken.
Systemic or oral corticosteroids are reserved for severe cases.
Inhaled corticosteroids are the most effective way to minimize the systemic adverse effects.
* Triamcinolone acetonide
* Beclomethasone dipropionate
* Budesonide
* Flunisolide
* Mometasone furoate
* Fluticasone propionate
* Ciclesonide
69
What are the adverse effects for inhaled corticosteroids (ICSs)?
* Candidiasis – can be treated with topical clotrimazole
* Can be reduced by having patients gargle water and expectorate after each inhaled treatment
* Ciclesonide – 21-ester prodrug, associated with less candidiasis.
* Hoarseness – direct effect of corticosteroids on the vocal cords
* Long-term use may increase the risk of osteoporosis and cataracts.
* In children, 1 cm reduction in their growth only for the first year.
70
How are leukotrienes produced?
Produced from arachidonic acid by 5-lipoxygenase
71
What are leukotrienes involved in?
Involved in many inflammatory diseases and in anaphylaxis.
72
What are examples of leukotrienes?
* LTB4 – potent neutrophil chemoattractant
* LTC4 and LTD4 – responsible for many symptoms of asthma, such as bronchoconstriction, increased bronchial reactivity, mucosal edema, and mucus hypersecretion.
73
What is the benefit of leukotriene pathway inhibitors?
* Improve asthma control
* Reduce the frequency of asthma exacerbations
74
T or F: Leukotriene pathway inhibitors are as effective as inhaled glucocorticoids.
False. Leukotriene Pathway inhibitors are not as effective as glucocorticoids.
75
How should leukotriene pathway inhibitors be taken for children?
Effective when taken orally, easier than inhalation for children.
76
How does aspirin-induced asthma?
Reduce significantly the response to aspirin in aspirin-induced asthma (5-10% of asthma patients)
77
What are the types of leukotriene pathway inhibitors?
* 5-lipoxygenase inhibitor – zileuton
* Selective antagonists for the cysLT1 receptor – zafirlukast, montelukast
78
What are the characteristics of the Zileutons?
Zileuton inhibits 5-lipoxygenase, which is crucial for converting arachidonic acid to leukotriene A4 (LTA4) the precursor of leukotrienes B4, C4, D4, and E4.
* 5-lipoxygenase inhibitor
* N-hydroxy group is essential for inhibitory activity.
* Good oral bioavailability
* Alternative to LABA in addition to inhaled corticosteroids
* Not for acute asthma attack
* Requires periodic monitoring of liver function.
* CysLTs – increase contraction, secretion and permeability
| Leukotriene Pathway Inhibitors
79
What are the adverse effects of Zileuton?
* Metabolized and inhibits some P450 isozymes
* Zileuton doubles the blood levels of theophylline and increases prothrombin time (PT) with warfarin use
* Side effects: headache and dyspepsia
Liver toxicity
80
What is the Zifirlukast?
* Blocks the binding of LTC4, LTD4, and LTE4 to the receptor
* Twice-daily dosing required
* Potential for liver toxicity (requires liver function monitoring)
* No boxed warning
* Less commonly prescribed compared to montelukast
* Benzofuran ring system with a sulfonamide group and a carboxyl group
81
What is Montelukast (Singulair)?
* Blocks the binding of LTC4, LTD4, and LTE4 to the receptor
* Once a day dosing
* Little liver toxicity
* Boxed warning for neuropsychiatric issues
* More commonly prescribed
* Developed from other weakly antagonistic quinoline derivatives
* Montelukast is a high-affinity, selective antagonist of the cysLT1 receptor.
82
What are the adverse effects of Zafirlukast/Montelukast?
* Not indicated for reversal of acute bronchospasm, but therapy can be contunued while treating with b2 agonists.
* Both are CysLT-1R antagonists
* Adverse effects: headache, nausea, diarrhea
* Food reduces bioavailibility-- do not take with meals
BOXED WARNING (added 2020)
* agitation, sleeping, mental health issues
* Dosing in the evening counters the neuropsychiatric issues
* The prescription is to dose in the evening- to counter increased leukotriene synthesis in the evening
83
What drug(s) is indicated for prophylaxis in both adults and children?
Zafirlukast/Montelukast
84
What are examples of methylxanthine drugs?
* Theophylline (most effective, more specific for smooth muscle)
* Theobromine
* Caffeine
Differ by position and number of methyl groups on their xanthine ring system.
85
How are methylxanthine drugs related to asthma treatment?
Once a mainstay of asthma tx but have almost been replaced by B2 selective agonists.
* Still used in some countries due to its low cost.
86
What is the mechanism for theophyline?
* Inhibition of phosphodiesterase (PDE3 and PDE4) --> increase in the cellular cAMP concentration --> bronchodilation and suppression of histamine release
* Block the action of adenosine, which causes bronchoconstriction and the release of histamine.
* Histone deacetylation, which suppresses inflammatory gene expression.
87
What does theophyline toxicity cause?
* N/V, Tremulousness, Arrhythmias
* Narrow therapeutic index
88
How does Magnesium/Aluminum hydroxide antiacids change theophyline absorption?
Mag/Alum delay theophyline absorption.
89
T or F: The half-life of Theophylline is delayed in CHF pts
False. The half-life of theophylline is prolonged in congestive heart failure patients
90
Does theophylline improve or aggravate pre-existing seizure disorders?
AGGRAVATE
91
How would an agent increase theophylline levels?
Many agents compete for the Cyp450 enzyme.
92
How do antimuscarinic agents work?
* Stimulation of cholinergic (parasympathetic) nerves causes bronchoconstriction and mucus secretion.
* Antimuscarinic drugs competitively inhibit the action of acetylcholine at muscarinic receptors.
* Clinically valuable for patients who are intolerant of inhaled β agonists.
93
What is ipratropium?
* Bronchodilator used for acute asthma exacerbations
* More common for COPD
* Quaternary amine derivatives of atropine (makes it highly hydropilic and poorly abs from the lungs after inhalation via solution or aerosol)
* Poorly absorbed into the circulation after inhaled.
* Minimal oral bioavailability
* Relatively free of systemic atropine-like effect
* N-isopropyl analog of atropine
94
What are examples of mast cell stabilizers?
* Cromolyn (Intal)
* Nedocromil (Tilade)
95
What are mast cell stabilizers used to treat?
* Prophylaxis of mild/moderate asthma, especially in children and EIA
* Inhibit mast cell degranulation.
96
Should mast cell stabilizer be dosed daily?
Yes
97
Are mast cell stabilizers absorbed poorly into systemic circulation?
Poorly absorbed into the systemic circulation and have little toxicity, but not as potent or as predictably effective as glucocorticoids.
98
What are mast cell stabilizers typically indicated for in the eyes?
Allergic rhinoconjuctivitis
99
Can cromolyns be taken orally?
No. Cromolyns are stable, insoluble salts; TF, they cannot be taken orally.
* Inhaled as microfine powder or aerosolized solution.
100
How does mast cell degranulation work?
Antigen mediated-binding of allergens to IgE antibodies bound to the cell surface releases inflammatory agents (histamine, kinins, serotonin, leukotrienes, prostaglandins)
* Ex. Binding of IgE antibodies to FceR. Binding of antigen to IgE antibodies. Clustering of FceR receptros. Influx of Ca2+ via Ca2_ release activated cannels (CRAC) ATP.
101
What are some triggers for mast cell degranulations other than allergens?
* Non-antigen mediated-thermal or mechanical stress
* Cytotoxic agents eg. venoms
Various drugs (e.g. high dose morphine)
102
What is a common anti-IgE monoclonal antibody?
Omalizumab
* Recognizes the portion of IgE that binds to its receptor (FceR-1 and FceR-2) on immune cells.
* Inhibits IgE binding to mast cells.
* Reserved for patients with severe asthma and allergic sensitization
103
When is monoclonal antibody therapy used in respiratory conditions?
* Modulates biological pathways by blocking receptors or cytokines
* Used when Steps 1-4 fail (ICS, leukotriene antagonists, etc.)
* Best for patients with frequent exacerbations
* Response may be lower in smokers, obese patients, or those with multiple allergies
104
Describe the type 2 low inflammation asthma phenotype.
Neutrophilic
IL-6, IL-8 and IL-17
* harder to treat and more likely to have adverse events when treatments have been used
105
Describe the type 2 high inflammation asthma phenotype.
Eosinophilic
IL-4, IL-5 and IL-13
* Also – PGD2 stimulation of the DP2 receptor
106
What happens when the asthma phenotypes overlap?
Overlap between phenotypes occur in atypical examples eg. Type 2 high with neutrophils due to occupational exposure
107
What are the 5 major types of biologics?
1. IgE antagonist - Omalizumab
2. IL-5 pathway - Reslizumab and Mepolizumab
3. IL-5 alpha receptor - Benralizumab
4. IL-4 receptor alpha antagonist – affects both IL-4 and IL-13 pathway – Dupilumab
5. Thymic stromal lymphopoietin (TSLP) - Tezepelumab
## Footnote
All five are approved for Type 2 high inflammation - bloody eosinophil level and/or elevated nitric oxide level from the GINA Guidelines
108
What is Omalizumab (anti-IgE monoclonal)?
* Over 20 years on the market
* Humanized mouse anti-human IgE antibody
* Given via SC injection – dosed based on body weight and IgE level
* Indicated for patients > 12 yrs. old with moderate asthma and unresponsive to inhaled steroids. (positive reaction to aeroallergen)
* One injection every 2-4 weeks. Self-injection version (2021)
* Binds to IgE and causes a 96% reduction in free IgE levels
109
What are the adverse effects of Xolair?
Anaphylaxis – 0.1% of patients – need to monitor the first few administrations
Other immune system-related adverse effects:
Injection site reactions
Increased incidence of infection
Some immunogenicity (urticaria, dermatitis, pruritus)
110
What do Th2 cells release to attract and activate eosinophils?
IL-5
111
What are examples of Anti-IL-5 humanized monoclonal antibodies?
* Mepolizumab (Nucala)
* Reslizumab (Cinqair)--> inj under supervision
* Benralizumab (Fasenra)
112
What are example of anti-thymic stromal lymphopoietin (TSLP)?
* Tezepelumab (Tezpire)
