Drugs for Asthma & COPD Flashcards
1
Q
How is asthma categorized pathologically?
A
Lymphocytic/eosinophilic inflammation and remodelling of the bronchial mucosa
2
Q
What are the clinical presentations of asthma?
A
Wheezing, dyspnea and cough
Mucus production
(Symptoms worsen at night)
3
Q
What are the mast cell IgE mediators?
A
Histamine
Leukotrienes
Interleukins
Prostaglandins
4
Q
What are the triggers of bronchoconstriction?
A
Cold Air
Exercise
Tobacco
Pollutants
5
Q
What are the mediators that lead to airway inflammation?
A
Cytokines
Leukotrienes
Interleukins
6
Q
Which are the inflammatory cells that infiltrate (asthma)?
A
Eosinophils
Leukocytes
Macrophages
7
Q
What are the mediators for bronchoconstriction?
A
Prostanglionic postsynaptic muscarinic receptors (M3) that are activated by Ach
8
Q
In order to prevent mast cell degranulation you would give:
A
Mast cell stabiliser
Prevents the release of mediators
9
Q
What is the anti-antibody given in asthma?
A
Anti-IgE
To prevent degranulation
10
Q
What do we give in case degranulation has already occurred and the mediators need to et inhibited?
A
PDE Inhibitors
Corticosteroids
Leukotriene modifiers
11
Q
What are the bronchodilators that are given in asthma?
A
Beta agonists
Muscarinic antagonists
Methylxanthines
12
Q
What are the anti-inflammatory agents given in asthma?
A
Release-inhibitors
Steroids
Slow-anti-inflammatory drugs
Antibodies
13
Q
What are the leukotriene antagonists given in asthma?
A
Lipoxygenase inhibitors
Receptor inhibitors
14
Q
What are the kind of drugs given in COPD?
A
Bronchodilators
Anti-inflammatory agents (steroids)
Antibiotics
15
Q
The inhaled route is preferred for which kinds of drugs?
Why?
A
β2 agonists
corticosteroids
–> To reduce risk of systemic effects
16
Q
Inhaled is the only possible route for which drugs?
A
Cromolyn
Anticholinergics
17
Q
Which dosage would be higher to achieve the same effect, oral or inhaled?
A
Oral
18
Q
Which patients are given drugs orally?
A
Those unable to use inhalers, small children, severe arthritis
19
Q
Which drug is ineffective inhaled and has to be given systematically?
A
Theophylline
20
Q
When is the parenteral route used ?
A
When the patient is severely ill, unable to absorb drugs via the GI route
21
Q
Inhalation therapy deposits drugs directly where:
A
Lungs
22
Q
The distribution of the inhaled drug is between which organs and depends on what?
A
Lungs and oropharynx,
Depends mostly on the particle size and efficiency of the delivery method
23
Q
What happens to the largest percentage of inhaled drugs?
A
Swallowed and absorbed and will enter the systemic circulation –> first pass effect
24
Q
How can inhaled drugs be given?
A
Metered-dose inhaler
Respimat
Nebuliser
Dry-powder inhaler
25
What is the distribution of the inhaled drug with the metered-dose inhaler?
10% to the lungs, 80% in the oropharynx and 10% in the device
26
What are Respimat inhalers?
Inhalers that deliver very fine mist --> extremely small particle size, decreased drug deposition in the mouth and the oropharynx
27
What does a nebuliser do?
It converts drug solution into mist --> smaller particle size --> less drug deposition in the mouth and oropharynx
28
What is the percentage distribution of the inhaled drug using the dry-powder inhaler?
20% in the lungs
Less than 80% in the oropharynx
Rest in the device
29
Which kind of inhaler requires hand coordination?
Metered-dose inhaler
30
Which inhaler cannot be used with a spacer?
Dry-powder inhaler
31
What is the function of a spacer?
Decrease particle size and increase speed --> less drug distribution to mouth and oropharynx --> less drug swallowed --> less drug absorbed from the GI --> limiting systemic effects
32
Which is the bronchodilator drug of choice when it comes to asthma?
Why?
β2 adrenergic agonists
They are long acting due to their high solubility
33
How do β2 agonists work?
Open Ca2+ activated K+ channels --> hyperpolarization
Decreased phosphoinositide hydrolysis --> increased Na+/K+ exchange, increased Na+, Ca2+ ATPase
Decreased myosin light chain kinase activity --> reduce contraction
34
Mechanism of Action of β2 agonists?
They activate the β2 receptors in the smooth muscle of the bronchial tree
They promote vasodilation and relieve bronchospasm
Suppress histamine release in the lungs and increase cilary motility
35
What are the examples of β2 agonists?
SABA & LABA
SABA: albuterol and salbutamol
LABA: salmeterol and formoterol
36
What is the duration of action of both kinds of β2 agonists?
SABA: 3 to 6 hours duration of action
LABA: >12hours duration of action
37
Clinical use for SABA?
Used as required based on symptoms and not on a regular basis, increased use --> more anti-inflammatory therapy
38
Which is the drug of choice in acute severe asthma?
SABA
39
What is one advantage of LABA over SABA?
Improved asthma control due to long duration
40
What is a contraindication of LABA?
They should never be used alone without ICS
41
What are the combination inhalers?
LABA + ICS
Salmeterol + Fluticasone (ADVAIR)
42
Why are combination inhalers used?
There is evidence of synergism and simplifies therapy
Ensures delivery of both ICS & LABA to the same cells
43
What are the side effects of β2 agonists?
Muscle tremor
Tachycardia and QT prolongation
Hypokalaemia
Hypoxemia
Metabolic effects
Tolerance/Resistance
44
What are the metabolic effects thatβ2 agonists can cause?
Hyperglycemia
Increased free fatty acids
45
Which kinds of drugs aren't recommended as monotherapy for asthma and why?
β2 agonists
They have no anti-inflammatory action
46
What are the examples of muscarinic receptor antagonists ?
SAMA & LAMA
SAMA: ipratropium
LAMA: tiotropium
47
What is the mechanism of action of SAMA?
Blocks all M subtypes including M2, which increases the risk of bronchoconstriction
48
How can SAMA cause bronchoconstriction?
M2 (which is blocked by SAMA) causes inhibition of Ach release,
Increase in acetylcholine --> constriction
49
Mechanism of action for LAMA?
Block M1& M3 and a little M2
50
Which other respiratory disease are LAMA approved for?
COPD
51
What are the side effects of anticholinergics?
Dry mouth
Irritation of pharynx
Increased intraocular pressure
Blurred vision
Constipation
Urinary retention
Tachycardia
Tolerance & Withdrawal
52
Side effects of ipatropium?
Bitter taste
The nebulised version can cause glaucoma
Paradoxical bronchoconstriction
53
When are muscarinic anticholinergics given in asthma?
If there is intolerance to inhaled β2 agonists
In status asthmaticus: additive effects with β2 agonists
54
What are the examples of methylxanthines?
Theophylline, Aminophylline, Caffeine
55
When are methylxanthines used in terms of sequence?
2nd line after LABA
56
Why are methylxanthines not used so often?
Need for plasma level monitoring, there is increase in side effects and poorly absorbed
Low therapeutic index !!
57
Sites of pharmacological effect of methylxanthines?
CNS
Cardiovascular
Pulmonary
GI
Renal
Skeletal
58
Main mechanism of action of methylxanthines?
Non-selective PDE inhibition
Adenosine receptors antagonism
59
What is the point of PDE inhibition with methylxanthines?
Increase in cAMP and cGMP --> bronchodilation
60
What is the benefit of adenosine receptor antagonism?
Adenosine causes bronchoconstriction by the release of histamine and leukotrienes
61
How does the release of IL-10 due to methylxanthine play a role in asthma?
IL-10 is an anti-inflammatory and is reduced during asthma, theophylline increases the release of IL-10.
62
What does NF-KB induce and why is it inhibited?
Induces pro-inflammatory genes, so theophylline inhibits the translocation of NFKB to the nucleus
63
What is the main role of adenosine?
Balances O2 need and availability
64
Which kind of drug is Adenosine inhibited by?
Methylxanthine
65
Which receptors does adenosine bind to?
A1& A2
66
What is the effect of adenosine on the lungs?
It releases histamine and leukotrienes --> causes bronchoconstriction
67
What are the side effects of theophylline?
Inhibition of phosphodiesterase
Blockage of adenosine receptors
Release of intracellular calcium
68
What happens if there is inhibition of phosphodiesterase?
Increase in HR and contractility
Relaxation of systemic arterioles
Nausea, vomiting and gastric discomfort
69
What happens if there is blockage of the adenosine receptors?
CNS stimulation
Increase HR & contractility
Diuretic effect
70
What happens if there is release of intracellular calcium?
increase in skeletal tone --> tremor
71
What increases the clearance of theophylline?
Enzyme induction, mainly CYP1A2 by co-administered drugs and smoking
72
What decreases clearance of theophylline?
CYP1A2 inhibition
Liver disease
Old age
73
Does theophylline have a high or low therapeutic index?
Low therapeutic index
74
What are two other examples of xanthine phosphodiesterase inhibitors?
Sildenafil (Viagra)
Pentoxyphilline (Trental)
75
Details about sildenafil?
PDE5 Inhibitor
Erectile dysfunction use
76
Details about pentoxyphilline?
Non-selective PDE inhibitor
Peripheral vascular disease use
77
What is the main purpose of corticosteroids in the treatment of asthma?
Mainly prophylactically as controller therapy
78
When do the benefits of ICS start?
Within 1 week but continue up to several months, their effects are more on a gene expression level thus it would take longer to appear.
79
What to do if asthma is not controlled by the dosage of ICS prescribed?
Add LABA
80
The adrenal cortex produces 3 classes of corticosteroids:
Glucocorticoids: cortisol
Mineralocorticoids: aldosterone
Adrogens: testosterone
81
The therapeutic indications of the corticosteroids produced by the adrenal cortex?
Endocrine: low dose; physiologic effect
Non-endocrine: high doses; pharmacologic effect
82
What are the therapeutic indications for non-endocrine glucocorticoids?
Rheumatologist Disorders
Allergic Conditions
Asthma
Dermatologic
Neoplasms
Allograft Rejection Suppression
83
Mechanism of action of non-endocrine glucocorticoids (ICS)?
Decreased synthesis and release of inflammatory mediators (histamine, leukotrienes and PG)
Decreased infiltration and activity of inflammatory cells (eosinophils and leukocytes)
Decreased edema (decrease in vascular permeability)
84
The sequence of events of the mechanism of action of ICS?
1. Corticosteroids bind to the glucocorticoid receptor (GR)
2. Receptor- ligand complexes translocate to the nucleus
3. Bind to coactivators
4. Inhibit HAT & recruit HDAC2
5. Reverse histone acetylation
6. Suppress activated inflammatory genes
85
What are the physiologic effects of ICS at higher systemic doses?
Hyperglycemia
Decreased muscle mass, myopathy
Thinning of skin
Potbelly, moon face, buffalo hump
86
What happens to the ICS dosage if there is increased stress?
Increase dosage
87
What are the local side effects of ICS?
Vocal cords atrophy --> hoarseness and dysphonia
Reflex cough and bronchospasm
Oral candidiasis
88
How do you prevent the local side effects of the ICS?
Decrease with spacer and mouth rinsing after inhalation
89
What is ciclesonide?
Pro-drug activated in brachial epithelia
90
Mechanism of action of ciclesonide?
When absorbed in the circulation, it binds to the serum proteins and has little access to receptors in the skin, eyes --> less side effects
91
What is the function of leukotriene modifiers?
They inhibit:
Bronchoconstrictiomm
Eosinophil infiltration
Mucus secretion
Airway edema
92
What are the examples of leukotriene modifiers?
5-LO Inhibitors
LT Antagonists
5-LO Inhibitors: Zileutron
LT Antagonists: Montelukast, Pranlukast, Zafirlukast
93
What is the function of zileuton?
Inhibits leukotriene synthesis
94
What is the function of zafirlukast & montelukast?
Leukotriene receptor blockers, the leukotriene has already been produced but they prevent it from binding to its receptors
95
What are the side effects of zileuton?
Liver injury,
Neuropsychiatric effects
CYP Interactions
96
What are the side effects of zafirlukast and montelukast?
Headaches and Gi
Liver injury (zafirlukast)
Churg-Strauss vasculitis
97
What is an example of Anti-IgE?
What is it?
Omalizumab
Humanised monoclonal antibody
98
How is Omalizumab given?§
Subcutaneously
99
What is the mechanism of action of Omalizumab?
Blocks the binding of IgE to high-affinity IgE receptors on mast cells and other inflammatory cells --> no degranulation
100
What are the common side effects of Omalizumab?
Injection-site reactions
Sinusitis, pharyngitis, headache
Cardiovascular (rare)
Anaphylaxis risk
101
What is the main risk factor of COPD?
Smoking
102
What is the FEV1/FVC ratio like?
Reduced
103
What is the difference between asthma and COPD?
COPD is irreversible and progressive
104
COPD comprises of:
Chronic bronchitis and emphysema
105
What is the pharmacotherapy for COPD
Smoking cessation!!
Bronchodilators
Corticosteroids
PDE4 Inhibitors
Mucolytics
106
Which bronchodilators are approved for COPD?
β2 agonists and inhaled anti-muscarinic drugs
107
Which drug are used to target nicotinic acetylcholine receptors and help smoking cessation?
Bupropion: antagonist
Varenicline: partial antagonist
108
When is bupropion prescribed?
1 to 2 weeks before quitting
109
When is varenicline prescribed?
1 week before quitting
110
What is the mechanism of action of the nicotine replacement drugs?
Allow for some or none of the sodium to pass through --> allow some or none of the smoking sensation (based on the degree of antagonism)
111
What is one risk of ICS when it comes to COPD?
May increase the risk of pneumonia / lower tract infections
112
Why can't ICS be used as mono therapy in COPD?
ICS are not effective in suppressing the inflammation of chronic bronchitis
113
When are ICS used in COPD?
Acute exacerbations
114
What is the example of PDE 4 Inhibitor?
Roflumilast: oral PDE 4 Inhibitor
115
When is roflumilast used?
To reduce exacerbations in patients with severe chronic bronchitis
116
Side effects of roflumilast?
GI disturbances and headache
117
What kind of drug is roflumilast?
An anti-inflammatory (increases cAMP levels)
118
What are mucolytics?
Drugs that breakdown the mucoprotein files in sputum, and decease viscosity making the sputum easier to be cleared
119
Examples of mucolytics?
Bromhexine, carbocysteine, erdosteine, acetylcysteine
120
What is the PK route of mucolytics?
Orally
121
What is the only exception of mucolytic PK route?
Acetylcysteine --> can also be given through a nebulizer
