Lecture 10 - Drugs & Asthma/COPD Flashcards
1
Q
What is COPD?
A
slow progressive airway obstruction due to chronic inflammation
2
Q
COPD is common in _____.
A
smokers
3
Q
Other causes of COPD?
A
air pollution and occupational exposures
4
Q
Symptoms of COPD?
A
- cough
- mucus hypersecretion
- dyspnea (shortness of breath)
5
Q
What does COPD include?
A
- chronic bronchitis (inflammation of bronchi)
- emphysema (destruction of alveolar structure - airways collapse during expiration)
6
Q
What is asthma?
A
chronic inflammatory disorder of the airways
7
Q
What is asthma characterized by?
A
recurring episodes of hyper responsiveness to stimuli that causes bronchoconstriction
8
Q
Symptoms of asthma?
A
recurring episodes of cough, wheezing, tight chest, dyspnea (shortness of breath)
9
Q
What is asthma based on?
A
triggering stimuli characterized as extrinsic (allergenic) or intrinsic (non-allergenic)
10
Q
extrinsic asthma = ?
A
allergenic
11
Q
intrinsic asthma = ?
A
non-allergenic
12
Q
Describe extrinsic asthma (allergenic)
A
- External stimuli such as environmental allergens (dust, mold, pollen, dander, foods) trigger plasma cells to produce antigen specific IgE antibodies
- Allergen & IgE binding to mast cells result in degranulation and release of inflammatory mediators
- Allergens typically have some glycoproteins that immune cells recognize as an antigen, a harmful substance that induced immune cells to produce antibody (IgE) that specially recognize the antigen
13
Q
Describe Intrinsic Asthma
A
- Non-allergenic asthma
- Symptoms triggered by non-allergenic factors (anxiety, stress, cold air, dry air, smoke, exercise, viruses)
- The mechanisms initiating the asthma attack are not completely understood:
- Abnormalities in the autonomic regulation of airway functions suggested to increase responsiveness.
- The innate immune system involved, the role of adaptive immune system remains elusive.
14
Q
What are the asthma symptoms amenable to drug therapy?
A
- Excessive airway smooth muscle tone
- Inflammation
- Mucus plugging
- Pulmonary edema
15
Q
Asthma & COPD Drugs:
Drugs divided based on treatment strategies?
A
1) controllers
2) relievers
16
Q
Asthma & COPD Drugs:
Drugs divided based on targets?
A
1) Airway muscle tone:
- Bronchodilators (Beta-adrenergic, methylxanthines, anticholinergics, leukotriene modifiers)
2) Inflammation:
- Anti-inflammatory agents (Corticosteroids, mast cell stabilizers, anti-IgE monoclonal-antibody, leukotriene modifiers)
17
Q
What are bronchodilators?
A
Agents that interact with smooth muscle cells lining the airways (bronchiole) and relax smooth muscles
18
Q
List some Beta-adrenergic bronchodilators
A
- Albuterol/Salbutamol
- Terbutaline
- Salmeterol
19
Q
List a Methylxanthine bronchodilator
A
-Theophylline
20
Q
List some anticholinergic bronchodilators
A
- Tiotropium
- Ipratropium
21
Q
List some leukotriene modifier bronchodilators
A
- Zileuton
- Zafirlukast
- Montelukast
22
Q
Sympathetic nervous system causes ________
A
bronchodilation
running from tiger, need air to breath
23
Q
Parasympathetic nervous system causes _______
A
bronchoconstriction
just relaxing to the max so you don’t need to breath too hard
24
Q
What receptor causes bronchodilation?
A
B2 (sympathetic)
25
What receptor causes bronchoconstriction?
M3 (parasympathetic)
26
Ca2+ increase causes _______
bronchoconstriction
27
Ca2+ decrease causes _______
bronchodilation
28
Describe how bronchoconstriction happens
Activation of parasympathetic nervous system:
- ACh binds to M3 receptors
- Activation of Gq
- PLC activation
- Increased DAG and IP3 hydrolysis
- increase of cytoplasmic Ca2+
- Ca2+ calmodulin activates myosin via MLCK
- myosin binds to actin --> actin slide past myosin
- contraction (that occurs as long as Ca2+ is present)
*Adenosine also increases Ca2+ levels (PLC activation via A1 receptor)
29
Describe how bronchodilation happens
- Activation of beta2 receptor, GPCR (NE, E)
- Activation of Gs
- AC activation
- ATP converted into cAMP - PKA activation:
1) promotion of SR Ca2+ pumps causes a decrease in cytoplasmic Ca2+
2) inhibition of MLCK, enzyme activation myosin, prevents myosin binding to actin
- dilation/relaxation
30
Albuterol/Salbutamol and Terbutaline are ____-acting
short
31
Salmeterol are ____-acting
long (12 hours)
32
MOA of B2 agonists
Stimulate AC thereby increasing the formation of cAMP which acts to relax the airway smooth muscle leading to bronchodilation
33
Route of admin of B2 agonists
Typically administered via inhalation:
- Albuterol and Terbutaline available in tablet form
- Terbutaline can also be administered SC
34
Indication of B2 agonists
- Extensively used in the treatment of asthma
- In inhaled form, Albuterol is the DOC for the treatment of acute attacks. For severe attacks, SC injection of Terbutaline or epinephrine may be required along with corticosteroids
35
What is the DOC for the treatment of acute asthma attacks?
Albuterol (inhaled form)
36
What is the DOC for the treatment of severe asthma attacks?
SC injection of Terbutaline or epinephrine may be required along with corticosteroids
37
We do we co-administer corticosteroids with anti-inflammatory drugs?
to prevent the development of desensitization and promote efficacy of B2 agonists
38
Adverse effects of B2 agonists?
- B1 receptors on the heart may get stimulated causing tachycardia
- skeletal muscle tremor
- tolerance may develop with very frequent use
39
Drug interactions with B2 agonists?
- Not effective on patient taking propranolol for HTN or other heart/circulatory conditions
- Co-administration of long term B2 receptor agonists with corticosteroids prevents desensitization.
40
Theophylline is a _____
Methylxanthine
41
Proposed mechanism of Theophylline (Methylxanthine)?
- Inhibits phosphodiesterase resulting in an increase in cAMP (cAMP acts to relax the airway)
- Inhibit adenosine receptors; systemic & CNS effects
* *Adenosine has been shown to cause the contraction os isolated bronchial smooth muscle and provoke the release of histamine from mast cells
- Can stimulate the contractility of diaphragmatic muscles
42
Route of admin of Theophylline?
Aerosol is the safest, other routes can adversely affect the heart & CNS.
43
Indication of Theophylline?
- Used as a second choice for the treatment of acute attacks. However, it has a narrow therapeutic window and pharmacokinetic slightly unpredictable (vary widely among similar patients) so it should be given under supervision
* *Can be given to Pts on propranolol
- COPD
- May reverse the steroid insensitivity
44
Adverse effects of Theophylline?
Common SE: headache, insomnia, tremors
Serious SE: anaphylactic shock, nausea & vomiting, stimulates heart, fever, seizures
Since it is metabolized by Cytochrome P450 enzymes, drug interactions may result in toxic concentrations
Caution: increased CV effects if given w B2 agonist
45
Ipratropium is a ____ acting anticholinergic
short
46
Tiotropium is a ____ acting anticholinergic
long
47
MOA of anticholinergics (ipratropium and tiotropium)?
- Blocks muscarinic receptors, preventing bronchial constriction and mucus secretion
- No effect on inflammation
48
Route of admin of anticholinergics (ipratropium and tiotropium)?
aerosol
49
Indication of Ipratropium
- For the treatment of COPD and chronic bronchitis
- The treatment of acute asthma attacks in children, adults and those that are intolerant of B agonists
- Ipratropium enhances the bronchodilation produced by B agonists. Therefore, this combination can be an effective treatment of severe asthma attacks.
50
SE of ipratropium
- Aerosol ipratropium is generally well tolerated, however, excessive use may cause atropine like effects (dry mouth, dilated pupils, tachycardia, stupor)
- Caution with glaucoma (Increased IOP)
- Caution in prostatic hypertrophy (urinary retention)
51
Leukotrienes are products of ______ ____ metabolism
arachidonic acid
52
Leukotrienes cause ??
bronchoconstriction, increased bronchial reactivity, mucosal edema and the secretion of mucus
53
MOA of leukotriene modifiers?
1) drugs that inhibit the synthesis of leukotrienes
| 2) drugs that block the receptors that leukotrienes act upon
54
How can NSAIDs induce asthma?
-they inhibit COX enzymes which means AA just goes to hydroperoxide and then to leukotrienes (slide 31)
55
Zileuton is a ??
leukotriene synthesis inhibitor
56
MOA of Zileuton
-inhibits 5-Lipoxygenase, which is the enzyme that catalyzes the formation of leukotrienes from arachidonic acid
57
Route of administration of Zileuton
orally active drug, administered 4 times a day
58
Indication of Zileuton
- The treatment of persistent asthma in adults and ASA-induced asthma
- Prevents exercise and antigen-induced bronchospasm
59
SE of Zileuton
Liver enzyme levels should be checked periodically for possibly hepatotoxicity
60
Drug interactions of Zileuton
Inhibits CYP450 which may interfere with the metabolism of other drugs (ex. theophylline, warfarin)
61
List 3 Leukotriene Receptor blockers
- Zafirlukast
| - Montelukast
62
MOA of Leukotriene Receptor blockers?
- Selective reversible inhibitors of the cysteine leukotriene-1 (CysLT1) receptor, thereby preventing leukotriene induced bronchoconstriction and airway wall edema.
- Prevents also chemotactic; infiltration of neutrophils and eosinophils
63
Route of admin of Zafirlukast
-Orally active, administered twice daily
64
Indication of Zafirlukast?
- Used for the treatment of mild to moderate asthma
- Less effective than corticosteroids
- Should not be administered to children under 8.
65
Adverse effects/drug interactions of Zafirlukast?
- Headache, GI disturbance
- Inhibits CYP450 which may interfere with the metabolism of other drugs (ex. theophylline, warfarin)
- Liver enzyme levels should be checked periodically for possible hepatotoxicity
66
Route of admin of Montelukast
orally active, administered once daily
67
Indication of Montelukast
- Modestly effective in the treatment of persistent asthma in children and adults.
- Less effective than corticosteroids.
- Should not be administered to children under 6 years of age.
68
Drug interaction/Adverse effects of Montelukast
- Inhibits CYP450 which may interfere with the metabolism of other drugs (ex. theophylline, warfarin)
- Liver enzyme levels should be checked periodically for possible hepatotoxicity
69
What do anti-inflammatory agents do?
Reduce inflammation, edema and mucus production
70
How do anti-inflammatory agents help in asthma?
They counteract airway inflammation and reduce asthma attacks and COPD flares/progression
71
List some corticosteroids
- Beclometasone
- Flunisolide
- Fluticasone
- Budesonide
- Mometasone
- Methylprednisolone
- Prednisone
72
List some mast cell blockers
- cromolyn sodium
| - nedocromil
73
______ = steroid hormones produced in the adrenal cortex
Corticosteroids
74
List 2 subtypes of Corticosteroids
Glucocorticoids
| Mineralocorticoids
75
What do glucocorticoids do?
regulate glucose metabolism
76
What do mineralocorticoid do?
salt & water balance
77
Corticosteroids are the _____ of anti-inflammatory process
King
78
Corticosteroids:
| Beclometasone, Flunisolide, Fluticasone, Budesonide, and Mometasone are all _________
inhaled
79
Corticosteroids:
| Methylprednisolone is given _____
IV
80
Corticosteroids:
| Prednisone is given ______
orally
81
MOA of corticosteroids
- blocks the release of arachidonic acid hence the production of leukotrienes
- increase the sensitivity of beta adrenergic receptors and prevents their desensitization
- prevents long term changes in airways structure & function
82
Corticosteroids:
| Route of admin
-Aerosol is the preferred mode of administration to limit systemic side effects, however severe exacerbations of asthma may require IV (methylpredisolone) or oral (prednisone)
83
Corticosteroids:
| Indication
- Aerosol used in most moderate cases of asthma and COPD
| - Corticosteroids are the first line of anti-inflammatory therapy for all ages
84
Corticosteroids:
| Adverse effects
- Aerosol administration of corticosteroids is safe. They may cause oropharyngeal candidiasis (thrush) and hoarseness
- Chronic use may result in the suppression of the adrenal glands and endogenous production of corticosteroids
- Common and permanent: Osteoporosis and cataracts in adults and growth retardation in children
- Common and reversible: edema, weight gain, psychological (mood swings, insomnia, anxiety) increased risk of infection, delayed wound healing, elevated BP, loss of glucose control in diabetics, glaucoma, and finally OMG muscle weakness
85
How can the adverse effects of corticosteroids be reduced?
with alternate day therapy for oral medication and morning administration (because AA is highest in the morning)
86
Who is cromolyn sodium approved for?
the treatment of asthma in all ages
87
Who is Nedocromil approved for?
Approved for the treatment of asthma in patients 12 and older
88
Mast cell blockers:
| MOA
- poorly understood
- inhibits the release of inflammatory mediators from mast cells, possibly by blocking ion-channels required for degranulation
89
Mast cell blockers:
| Route of admin?
aerosol, administered 2-4 times/day
90
Mast cell blockers:
| Indication
- For the treatment of mild-moderate asthma
- Dose not reverse an ongoing broncho-constriction, BUT, regular use reduces bronchial hyper-reactivity and inhibits acute and chronic responses
- Less potent than inhaled glucocorticoids in controlling asthma
- Trial period of 4-6 weeks is required to determine its efficacy
- Anti-inflammatory DOC for the treatment of allergenic asthma in children (>2-3 yrs old)
- Also helpful to prevent exercise-induced asthma
91
Mast cell blockers:
| Adverse effects?
- Generally well tolerated.
- Can cause throat irritation, dryness, cough, nasal secretions and congestion, nausea
Serious adverse effects are rare:
- Anaphylaxis, hives, low BP, tightness in chest
- Less than 2% experience reversible dermatitis, myositis, or gastroenteritis
92
Omalizumab (Anti-IgE Monoclonal antibody):
| MOA
Selectively binds human free IgE and thus prevents IgE binding to cells and reduces IgE levels. Both acute and prolonged inflammatory responses reduced.
93
Omalizumab (Anti-IgE Monoclonal antibody):
| Indication?
Used for allergic asthma
94
Omalizumab (Anti-IgE Monoclonal antibody):
| Route of admin?
SC injections
95
Omalizumab (Anti-IgE Monoclonal antibody):
| Adverse effects?
may cause anaphylaxis in some patients
96
Goals of therapy with asthma & COPD?
1) Maintain normal activity levels
2) Maintain near normal pulmonary function rates
3) Prevent troublesome symptoms - cough, breathlessness @ night or during exertion
4) Avoid adverse effects of medications
5) Avoid drug interactions
97
What is the treatment for mild COPD?
Bronchodilators as needed
98
What is the treatment for moderate COPD?
Bronchodilators and anti-inflammatory drugs
99
What is the treatment for severe COPD?
antibiotics, bronchodilators and anti-inflammatory drugs and oxygen therapy
100
Asthma = ______
reversible
101
COPD = ______
irreversible
102
see slide 57
alrighty
