U2 Asthma Flashcards
1
Q
What are obstructive respiratory diseases?
What are some examples?
A
diseases affecting the movement of air in and out of the lungs
Asthma and COPD
2
Q
What are restrictive respiratory diseases?
What are some examples?
A
diseases affecting total lung capacity
e.g. lung cancer and pulmonary fibrosis
3
Q
What is asthma caused by?
A
lung inflammation
4
Q
Why can obstructive lung diseases such as asthma develop restrictive features in severe disease?
A
due to damage to lung architecture caused by prolonged lung inflammation
5
Q
What is the main characteristic of asthma?
A
episodic periods of breathing difficulties
6
Q
What is the asthma causing inflammation due to in those who have the condition?
A
generally type 1 hypersensitivity
7
Q
What is an asthma attack?
A
manifestation of bronchoconstriction which is caused by inflammation in generating smooth muscle contraction
8
Q
What is bronchoconstriction?
What does it cause?
A
Narrowing of the airways (reduced airway diameter)
causes increase in restriction to airflow
9
Q
What two factors, caused by inflammation during type 1 hypersensitivity reactions, cause bronchoconstriction and consequently reduced airflow?
A
- smooth muscle contraction
- increased mucous production
both result in decreased airway diameter
10
Q
what is resistance to airflow proportional to?
A
1/airway radius ^4
11
Q
What are airflow needs determined by?
A
metabolic rate
12
Q
How does the brain increase airflow in response to exercise?
A
- increased rate and depth of breaths
- release of adrenaline
13
Q
How does the release of adrenaline cause bronchodilation?
A
adrenaline activates beta2 adrenoreceptors on airway smooth muscle
14
Q
what is the formula to calculate airflow?
A
pressure gradient / resistance (determined by airway diameter)
15
Q
what influences the pressure gradient between the chest cavity and the atmosphere?
A
diaphragm, internal and external intercostal muscles
16
Q
How is airflow measured clinically?
A
spirometry
17
Q
what is meant by ‘peak flow’ ?
A
maximum rate of exhalation
18
Q
What is FEV1?
A
volume of air that can be forcibly exhaled in 1 sec
19
Q
What is the process of resting inhalation?
(consider air pressure and pressure in thoracic cavity)
A
atmospheric pressure > pressure in chest
diaphragm moves down and out and external intercostal muscles contract
air moves in, lungs expand, chest volume increases
20
Q
What body parts are involved in resting respiration?
A
diaphragm and external intercostal muscles
21
Q
What is the process of resting exhalation?
(consider air pressure and pressure in thoracic cavity)
A
pressure in chest > atmospheric pressure
diaphragm moves in and up (relaxes), external intercostal muscles relax
elastic recoil repels air, air moves out
22
Q
How is the process of exhalation when exercising different from exhalation when at rest?
A
(diaphragm and external intercostal muscles relax)
- internal intercostal muscles contract
- abdominal muscles contract
air is forced out
23
Q
In order for asthma patients to get the same airflow as is normal (to compensate for increased resistance), what must change?
A
the pressure gradient between the atmosphere and the thorax has to increase
24
Q
External intercostal muscles are located where?
What is their role?
A
On the outside of the ribs
Pull ribcage up and out
25
Internal intercostal muscles are located where?
What is their role?
inside the ribcage
pull the ribcage down and in
26
The increase in demand of the intercostal muscles to generate a greater pressure differential to overcome increased airflow resistance in asthma patients has what effect on the person?
breathing difficulties - they have to work harder to generate the airflow required by the body
27
What three sorts of inhalers can be used to treat asthma?
1. relievers
2. preventers
3. combi-inhalers
28
What colour are reliever inhalers?
How do reliever inhalers work?
What is an example of a reliever?
blue
- cause bronchodilation - relieve acute asthma symptoms
- no anti-inflam action - no affect on disease progression
Salbutamol - long acting beta agonist
29
What colour are preventer inhalers?
How do preventer inhalers work?
What is an example of a preventer?
brown
- anti-inflam action; limit disease progression
- no affect on airway diameter therefore no acute relief of symptoms
mostly corticosteroids e.g. beclametasone, fluticasone
30
What do combi-inhalers contain?
How do combi-inhalers work?
What is an example of a combi-inhaler?
both preventer (steroid) and reliever (long acting beta agonist
provide long term bronchodilation and prophylaxis by limiting pulmonary inflam
Symbicort
31
What is the advantage to using an inhaler?
What type of delivery is this?
- delivered to target site without need to be transported around body in blood
- reduces risk of side effects
topical
32
Why might systemic symptoms due to inhaled steroids become apparent?
Due to high doses and increased absorption
33
What kind of inhaler would be needed to relieve the symptoms of an asthma attack?
Within how long will relief become noticeable?
How long can the relief last?
reliever
within minutes
from an hour to twelve depending on drug
34
Why shouldn't long-acting beta agonists be taken without a steroid?
ie. why is it recommended to have both a reliever and a preventer or one combi-inhaler?
What could be the consequence of this?
long-acting beta agonists can mask the progression of asthma
- patient unaware of progression
serious asthma attack once bronchodilation cover insufficient
35
What does SABA stand for?
short acting beta agonist e.g. salbutamol
36
What does ICS stand for?
inhaled corticosteroids
37
What two treatment-related factors are thought to be contributory to asthma related deaths?
1. underuse of ICS
2. overuse of SABA
SABA monotherapy is now outdated
38
What does LABA stand for?
What is an example of this?
long acting beta agonist
(will be fast acting)
formoterol
39
What is the preferred treatment options for those with a new asthma diagnosis?
ICS plus LABA - formoterol
40
The first step in the treatment ladder for asthma will be what from November 2024?
ICS/Formoterol prn
41
How has the use of formoterol influenced daily dosage needs for ICS?
decreased
42
How do ICS reduce the severity and frequency of asthma attacks?
- limits pulmonary inflam
- reduces airway remodelling and disease progression
43
What are the most common active ingredients in combi-inhalers?
budesomide with formoterol
44
Why is it important to prescribe combi-inhalers by brand?
to ensure patients get same inhaler device from pharmacy, not all brands have same APIs
45
How many people in the UK have asthma?
5.4 million
46
How many households are affected by asthma?
1/5
47
How many people a day die from asthma?
3
48
What percent of asthma-related hospital admissions are estimated to be avoidable?
75%
49
What percent of asthma deaths are preventable?
up to 46%
50
For what three reasons are asthma statistics so bad?
1. poor patient compliance
2. incorrect inhaler use
3. steroid resistance
51
How extensive is steroid resistance among asthma patients?
What can steroid resistance look like?
not very, only in small proportion of patients
ranges from reduced response to no response at all
52
WHO estimates that patient compliance for long-term treatments such as ICS for asthma is as low as what?
50%
53
Why is patient compliance with ICS use so poor?
- wary of steroid-associated side effects
e.g. those associated with abuse of anabolic steroids in sports (not the same)
or serious effects of systemic use of CS
- comparing to relief felt from relievers; believe preventer not helpful (passive drug effect)
- do not believe in the risks associated with asthma
54
How can poor patient compliance be combated?
education about disease and the way in which ICS needed to manage it
55
In what two circumstances could a patient see the serious effects of systemic use of corticosteroids?
1. high dose ICS
2. short-term use of oral corticosteroids to combat acute exacerbations
56
What is the possible consequence of incorrect inhaler technique?
subtherapeutic dose, even if patient fully adherent
57
How do metered dose inhalers as preventers work?
deliver medicine in a puff under pressure
58
How do dry powder preventer inhalers work?
force of the patient's inspiration is required to pull the drug away from its carrier
59
What is the simplest way of classifying asthma phenotypes?
Extrinsic / allergen-induced
Intrinsic / non-allergy induced
60
What are some common triggers for allergen induced asthma?
- pollen
- house dust mites
- mould
- ragweed
61
What are some common triggers for non-allergen induced asthma?
- viral infection
- cold, dry air
- pollution
- aspirin
- cigarette smoke
- exercise
62
Why is there a considerable overlap in the triggers between extrinsic and intrinsic asthma?
Hyperresponsiveness
63
What is the definition of a phenotype?
One or more symptoms caused by an interaction between genetics and the environment
64
What is the definition of an endotype?
A subclass of a disease based on differences in functional response or pathological mechanism
65
What is early phase bronchoconstriction during an asthma attack?
How long does it take to resolve?
What causes it?
Rapid bronchoconstriction manifested as difficulty breathing
- resolves after about 30 mins
Caused by exposure to an allergen that the asthmatic is sensitive to
66
What are the characteristics of a delayed phase bronchoconstriction in an asthma attack?
- no re-exposure to allergen; continuation of previous allergen-induced inflam
- often 6-8 hours after early phase
- lasts longer than early phase
- often occur at night
67
What is thought to be the cause of delayed phase bronchoconstriction?
Inflammatory mediators released by mast cells during early phase
- causes chemotaxis of other inflam cells to lungs
Including EOSINOPHILS
- temporally associated with delayed phase bronchoconstriction
68
What is PEFR? What are its units?
What can it be used to indicate?
Peak Expiratory Flow Rate (litre/min)
Volume of air forcefully expelled from the lungs in one quick exhalation
Can indicate ventilation adequacy and airflow obstruction
69
What is the average value for PEFR?
( ie when not having an asthma attack)
400 litres/min
70
How does the value for PEFR change for patients during
1. Early phase bronchoconstriction
2. Delayed phase //
1. Dramatic decrease until <25% of normal rate, short term then dramatic increase back to normal
2. Fairly dramatic decrease until around 25% (+) of normal rate, prolonged attack with PEFR increasing slowly over a few hours back to normal
71
What is FEV1?
What can it be used for?
Forced Expiratory Volume in 1 sec
Can be used to categorise the severity of obstructive lung diseases
72
Hyperresponsiveness is a key characteristic of asthma. What does it mean?
Responses by asthmatic patients to environmental stimuli are exaggerated (to level of attack)
- more severe
- occur in response to smaller amounts of stimuli
73
Allergic asthma is nearly always linked with..?
There is quite a strong link between asthma and …?
Other allergies e.g. hay fever
Childhood eczema
74
What is the first half of the process of sensitisation?
1. Dendritic cells in lung recognise foreign allergen
2. Dendritic cells present allergen to undifferentiated T cells (Th0) @ lymph nodes
3. T helper cells differentiate into Th2
4. Th2 activate B cells to generate IgE that binds the specific allergen
75
What part of the sensitisation process differs between asthmatic and non-asthmatic patients?
When B cells have generated specific IgE, in non-asthmatics
- regulatory process preventing inappropriate inflam processes being mounted against benign proteins
76
What is the second half of the process of sensitisation?
1. IgEs bind to surface of mast cells via receptors
2. Allergen binds to IgE upon re-exposure ; cross-linking of receptors
3. Degranulation, activation triggered
77
What kinds of receptors does the Fc region of IgE bind to on the surface of mast cells?
High affinity Fc epsilon RI
78
Apart from mast cells, what other cells do IgE bind to?
Via what receptors?
Eosinophils via low affinity Fc epsilon RII
79
What is the primary event in triggering an allergic asthma attack?
Activation and Degranulation of mast cells by allergen-induced cross-linking IgE receptors on the surface of mast cells
80
What triggers the arachidonic acid cascade?
What is the result of this?
(See cascade in U2 L2 slide 7)
Mast cell activation - activates membrane-bound phospholipase A2
Results in production of other inflam mediators
81
What is the role of leukotrienes and prostaglandins as inflam mediators?
- promote and drive inflam response or
- terminate or limit it
82
What leukotriene receptor is important in bronchoconstriction and recruitment of eosinophils?
CysLT1 receptor
83
What is one example of a drug target for asthma?
CysLT1 leukotriene receptor
(Used clinically in asthma treatment)
84
How can glucocorticoids stop the activation of the arachidonic acid cascade?
By preventing the activation of membrane-bound phospholipase A2
85
What inflammatory responses is histamine responsible for? (Not exclusively)
- vasodilation
- increased vascular permeability
- leukocyte recruitment
- increased mucous production by goblet cells
- bronchoconstriction
86
What inflammatory responses do leukotrienes play a part in? E.g. LTC4, LTB4
- vasodilation
- increased vascular permeability
- leukocyte recruitment
- increased mucous production by goblet cells
- bronchoconstriction
87
What inflammatory responses is IL-8 responsible for? (Not exclusively)
- increased vascular permeability
- leukocyte recruitment
88
What inflam mediators are directly responsible for bronchoconstriction?
Histamine
PGD2
LTC4
Tryptase
89
How are eosinophils drawn into the lungs during delayed bronchoconstriction?
From circulation via expression of proteins on surface of pulmonary blood vessel endothelium
90
How do eosinophils contribute to delayed (late phase) bronchoconstriction?
What other athsmatic characteristic is this thought to contribute towards?
Eosinophils release inflam mediators which can damage the epithelial layer - reduces integrity of protective barrier
Hyper-responsiveness
91
What are the consequences of reduced epithelial layer integrity in the lungs?
(Indirectly caused by eosinophils)
- Oedema from pulmonary vessels due to increased leakiness therefore
- increased bronchiole wall thickness reducing airway diameter and therefore
- delayed bronchoconstriction
92
What is the role of both sympathetic and parasympathetic nerves in delayed bronchoconstriction?
Both activated - increase in inflam mediator and acetylcholine release from sensory nerve fibres therefore
- increased smooth muscle contraction
- increased mucous secretion
93
What receptors, activated by the parasympathetic system, contribute towards bronchoconstriction?
ACh, M3
94
How do eosinophils (as well as other inflam cells) contribute towards hypersensitivity?
- release of cytotoxic mediators
- causes damage to epithelium
- causes hyper-reactivity
95
How do eosinophils contribute towards increased severity and frequency of asthma attacks?
- release of remodelling mediators
- causes fibrosis, hypertrophy of bronchial wall
- increased freq and severity of attacks
96
What are the main effects of inflammatory-driven changes to the structure of the lungs and airways?
- airway wall is thicker, reduced diameter, increased flow resistance
- lungs less stretchy therefore reduced capacity & reduced elastic rebound when exhaling
97
How does chronic inflammation affect the process of mucus production as well as the mucus produced?
1. increased # of goblet cells
2. more viscous, less mobile mucous - increased airway occlusion
98
What is pulmonary angiogenesis?
What causes it?
creation of new blood vessels in the lungs
chronic inflammation
99
What are the consequences of pulmonary angiogenesis?
- increased oedema in airway wall
- increased SA for eosinophils to access lungs
100
How does chronic inflammation affect smooth muscle cells?
What is the effect of this?
hypertrophy (increase in cell size) and hyperplasia (increase in cell number)
reduced airway diameter, increased strength of bronchoconstrictor responses
101
What repair process that functions alongside inflammation has a negative effect on lung capacity?
Why?
activation of fibroblasts - increase in fibrosis
counter-productive as lungs need to be stretchy;
lungs will have
- reduced capacity to expand
- impaired elastic rebound
102
What is the overall consequence of changes in lung structure?
What is the main goal of therapy for asthmatics?
progressive worsening of asthma symptoms in response to repeated attacks
to break the cycle of inflammation to prevent (at least limit) airway remodelling
103
How can inflammation of the lungs and airways become chronic?
repeated cycles of allergen exposure that do now allow sufficient time for resolution of the inflammatory response
104
What is the most common reliever medication used in asthma treatment?
Into what groups are they divided?
beta2-adrenoreceptor agonists
Divided into short and long-acting AKA SABA and LABA
Most common SABA is Salbutamol
105
Why must LABAs never be prescribed without an ICS?
LABAs mask the symptoms of asthma; allows condition to worsen without being detected therefore increasing rates of morbidity/mortality
106
What are Xanthines?
Are they used for asthma treatment?
Class of drug that includes caffeine
Not caffeine but other two members of this drug class are
107
Why does the parasympathetic system have more of an effect on airway muscle tone?
Has direct innervation of bronchial smooth muscle via vagus nerve (unlike sympathetic)
(Sympathetic efferent nerves may control vasomotor tone only)
108
What is the effect of the activation of Muscarinic M3 receptors on smooth muscle tone in the airways?
- bronchoconstriction
- increased mucous production
- vasodilation of bronchial vessels
109
Where are beta-2 adrenoreceptors located?
What is the effect of their activation?
Expressed abundantly on airway smooth muscle
Stimulation e.g. by adrenaline (mediator) causes bronchodilation
110
What is the effect of M3 receptor antagonists?
Bronchodilation ie. Same as beta 2 adrenoreceptor agonists
111
In what sorts of variants are muscarinic antagonists available?
When would muscarinic antagonists be used clinically? Why?
Short and long-acting ie SAMA, LAMA
Used more in COPD treatment because
Lungs of COPD patients have increased cholinergic tone than those of asthma patients (ACh acts on muscarinic receptors) therefore more effective
112
What is the effect of activation of the CysLT1 receptor on airway smooth muscle?
What bocks this receptor?
How do leukotrienes usually act on this receptor?
Bronchoconstriction
Leukotriene receptor antagonists
High affinity agonists - contribute to inflammation-induced bronchoconstriction
113
What can be used as drug targets for asthma?
1. Beta2 adrenoreceptors - agonists
2. Muscarinic M3 receptors - antagonists
3. CysLT1 leukotriene receptors - antagonists
114
Are there any histamine receptors that can be used as drug targets in asthma treatment?
No;
H1 - antagonists have no effect on bronchoconstriction
H4 - antagonists did not make it past clinical trials (no beneficial effects)
115
What is the general mechanism by which relievers generate bronchodilation?
Reduce cytosolic levels of calcium in airway smooth muscle cells
- calcium needed for contraction via actin myosin network filaments
116
Xanthines are known to be able to block adenosine receptors. What is the effect of this in
- asthmatic patients
- non-asthmatics
Antagonism of adenosine receptors causes
Asthmatics - bronchodilation
Non-asthmatics - bronchoconstriction
117
How does activation of Beta2 adrenoreceptors lead to the activation of protein kinase A, PKA?
1. agonist activates B2 adrenoreceptor on plasma membrane
2. Activates G protein, Gs
3. activates membrane-bound enzyme adenyl cyclase
4. generation of cAMP from ATP
5. cAMP activates PKA
118
What enzyme regulates levels of intracellular cAMP?
phosphodiesterase (PDE)
119
What is one mechanism for which xanthines e.g. theophylline generate bronchodilation?
block PDE, increasing levels of cAMP in the cell
120
What is the approximate duration of action for SABAs e.g. Salbutamol?
4-6 hours
121
Why does the hydrophilic nature of Salbutamol contribute towards it being short-acting?
1. limited tissue retention - does not form depot in airway tissues therefore not in close proximity to receptor for extended period
2. rapid clearance - relatively quick elimination from body
122
What is the approximate duration of action for LABAs e.g. Salmeterol?
12 hours
123
Why does the lipophilic nature of LABAs allow them to be relatively long acting?
they can get into the plasma membrane as a depot and leech out slowly
124
LABAs must not be prescribed without what?
Why?
Corticosteroids e.g. ICS
because long-lasting bronchodilating action can mask worsening asthma symptoms
125
Why are side effects of beta2-adrenoreceptor agonists limited?
topical administration to the lung
126
What side effects may occur due to overuse or oral dosing of beta2-adrenoreceptor agonists?
- shakiness
- tachycardia
- headaches
- muscle cramps
127
For how long will cAMP continue to be generated from ATP by the enzyme adenyl cyclase?
for as long as the beta2 adrenoreceptor is occupied
128
Through what two mechanisms does the activation of protein kinase A, PKA, reduce free cytosolic calcium levels?
1. phosphorylation of K+ channels
2. reduction of phosphoinositol hydrolysis
129
What is the effect of having reduced levels of free cytosolic calcium?
reduced muscle contraction
130
How does the phosphorylation of K+ channels by PKA lead to a reduction in free cytosolic Ca2+?
- phosphorylated K+ channels lead to increase in K+ efflux
- membrane becomes hyperpolarised (-)
- hyperpolarisation inhibits voltage sensitive Ca2+ channels
- reduced Ca2+ influx into cytosol
131
How does the reduction of phosphoinositol hydrolysis by PKA lead to a reduction in free cytosolic Ca2+?
- reduced phosphoinositol hydrolysis means reduced generation if inositol triphosphate, IP3
- reduced binding of IP3 to receptors on ER which serve as calcium release-channels
- reduced release of Ca2+ from stores into cytosol
132
What is the role of inositol triphosphate, IP3 in muscle cells?
cause the release of Ca2+ from stores into the cytosol
133
What is the role of myosin light chain kinase (MLCK) ?
to phosphorylate part of the myosin filament, allowing for binding to actin and formation of cross bridge therefore muscle contraction
134
How does the inhibition of MLCK reduce the size of muscle contraction?
- reduced phosphorylation of myosin filament
- reduced # of cross-bridge formation
- reduced size of muscle contraction
135
How does increasing the activity of the Na/K pump cause hyperpolarisation?
2 Na out for every 3 K in
- increased conc gradient of K+ compared to extracellular
- increased polarisation (-) of smooth muscle membrane
- eventual increased efflux of K+
- resting membrane potential becomes more negative than before
136
What is the effect of phosphodiesterase inhibition?
- higher cellular levels of cAMP
- increased activation of PKA
- increased inhibition of smooth muscle contraction
137
Phosphodiesterase inhibitors are not yet used to treat asthma. What are they used for?
How do they work?
erectile dysfunction e.g. Viagra
inhibits phosphodiesterase, driving muscle relaxation
138
What is the API in viagra?
sildenafil
139
Why is there some selectivity of action for PDE inhibitors?
there are many isoforms of PDE
140
As well as action at B2 adrenoreceptors, beta 2 agonists have another positive effect for asthmatic patients - what is it?
How does it work?
increase mucous clearance from the lung
increasing the rate at which epithelial cilia beat
141
What are the two types of xanthine that can be used clinically to treat asthma?
Which is more soluble?
Theophylline and aminophylline
aminophylline
142
why are xanthines inherenly difficult to dissolve?
hydrophobic nature
143
Why is the clinical use of theophylline limited?
1. therapeutic index is low
2. is a substrate for CyP450 therefore subject to many interactions
144
What is meant by therapeutic index?
difference between an effective dose and a toxic dose
145
What is the effect of smoking on cytochrome P450?
What does this mean for smokers being treated with theophylline?
it is upregulated
smokers require a higher dose than non-smokers
146
What is the role of Cytochrome P450 enzymes?
metabolise about 90% drugs
147
What is the possible consequence of a known smoker being treated with theophylline giving up smoking?
theophylline overdose as CYP450 levels would return back to normal levels - therefore less drug metabolism
148
What are the possible adverse effects of theophylline?
- GI symptoms e.g. nausea, stomach pain
- neuronal effects e.g. sleeplessness, restlessness
- cardiovascular effects e.g. tachycardia and cardiac dysrhythmias
149
What is the clinical use of aminophylline as asthma treatment?
in asthma emergencies where it is delivered as a slow IV infusion
150
PDE inhibition is thought to be unimportant in therapeutic brochodilation but what ares the other areas in which it may be important?
- limiting inflammation
- reducing corticosteroid resistance
151
What is a plausible MOA for xanthines in asthmatic treatment?
adenosine receptor activation leads to bronchoconstriction
xanthines are adenosine receptor antagonists
152
What are SAMAs and LAMAs?
short-acting muscarinic antagonists and long-acting muscarinic antagonists
153
What is an example of a SAMA?
Approx how long is their duration of action?
Ipratropium
3-5 hours
154
What is an example of a LAMA?
Approx how long is its duration of action?
Tiotropium
24 hours +
155
Why can SAMAs and LAMAs be delivered via inhalation?
- not selective for different subtypes of muscarinic receptor
- chemical comp limits absorption into pulmonary circulation; reduced chance of adverse effects
156
What are the more common adverse effects of muscarinic antagonists associated with?
What are some examples?
systemic blockade of muscarinic receptors e.g.
- headaches
- cough
- dry mouth
157
What is the general MOA of SAMAs and LAMAs in bringing about any sort of bronchodilation?
block M3 receptor subtype on bronchial smooth muscle, preventing ACh from binding and causing bronchoconstriction
158
What neurotransmitter usually acts on M3 receptors to cause bronchoconstriction?
ACh from parasymp nerves
159
Why are SAMAs and LAMAs more commonly used in the treatment of COPD than asthma?
The more parasympathetic tone there is, the more effective the SAMA/LAMA will be
COPD patients tend to have more parasympathetic tone than asthmatic patients
- SAMA and LAMA more effective for COPD
160
Why is the effect of greater bronchodilation limited when increasing doses of muscarinic antagonists?
- inhaled MAs have access to M2 receptors because no selectivity for muscarinic receptor subtypes
- increasing MA dose increases antagonism of M2 receptor
- increased release of ACh therefore increased competition with MA for M3 binding
161
What is the role of the presynaptic M2 receptor?
limits release of ACh into synapse
ie. reduces release at moderate, high frequency of stimulation
(ACh binds to M3 causing bronchoconstriction)
162
For what reasons is asthma control an important clinical goal?
1. improves quality of life
2. reduces risk of early death
3. reduces costs associated with morbidity
163
What are the main goals of preventer medication?
1. limit pulmonary inflam
2. reduce remodelling
3. reduce disease progression
4. reduce severity and freq of attacks
164
Why is it important for asthma patients to receive a flu jab each year?
can control asthma exacerbations where even mild asthmatics can be hospitalised due to resp infection
165
Unless patients are on high doses of ICS, what is the worst symptom patients are likely to experience?
What is this due to?
How can it be avoided?
sore throat due to opportunistic Candida
localised immune suppression
rinsing out the mouth after taking the ICS
166
Where is the receptor for glucocorticoids located?
How do glucocorticoids reach such receptors?
intracellular
they are hydrophobic so can diffuse into cell via lipid bilayer of cell membrane
167
What happens to glucocorticoids following intracellular receptor binding?
1. receptor becomes activated
2. receptors dimerise
3. receptors translocate to nucleus
4. dimerised receptors bind to glucocorticoid response elements in DNA and influence gene transcription related to inflam
168
Through what two mechanisms is transcription influenced by dimerised glucocorticoid receptors?
1. increase transcription rates of anti-inflam gene products e.g. IL-10 by binding to glucocorticoid-response elements in the promoter region of steroid-sensitive genes
2. reduce transcription of pro-inflam gene products e.g. cyclo-oxygenase 2 (COX-2) and inducible nitric oxide synthase (iNOS) via interaction with negative glucocorticoid-response elements
169
Why do ICS take several days to become effective?
- takes time to transcribe, translate and make anti-inflam proteins
- pro-inflam prpteins must be removed and not replaced before apparent effect
170
What is one feature that can indicate whether a patient is getting benefit from ICS?
Why is this?
reduction in night-time asthma attacks
correct use of ICS should reduce/abolish late phase bronchoconstriction (usual cause)
171
How does the effective use of ICS reduce the severity and freq of attacks?
- significant decrease in # of inflam cells in lungs
- inflam response needs to reach threshold to generate bronchoconstriction sufficiently for patient to notice
172
What effects can ICS have on structural cells?
What are the consequences of these for the patient?
(nb epithelial layer actively contributes towards inflam and imms sys)
1. reduced release of humoral mediators of inflam from epithelial cells
2. reduced permeability of pulmonary endothelium; reduced oedema in bronchiole walls
3. increased expression of beta2-adrrenoreceptors on smooth muscle cells - more responsive to relievers
4. reduced mucous secretion from goblet cells
173
What two factors affect the effectiveness of glucocorticoid action?
1. receptor binding affinity
2. lipophilicity
174
How does lipophilicity affect glucocorticoid action?
high lipophilicity means a corticosteroid is better able to access the intracellular receptor meaning less drug is required
174
How does receptor binding affinity affect glucocorticoid action?
the higher the affinity, the smaller the amount of drug is needed to activate the receptor
175
Beclomethasone is a prototypical CS, fluticasone propionate is a new generation CS - why is a much lower dose of FP needed compared to Beclomethasone?
FP has
- much higher receptor affinity
- similar lipophilicity
176
How is moderate dose Beclomethasone equivalent to high dose FP?
in terms of ICS molecules;
moderate dose BP - 800
max dose FP - 1000
equivalent because FP more potent
177
What factors, other than receptor affinity and lipophilicity, influence dose received from an inhaler?
inhaler technique
178
in terms of beclomestasone, how can poor inhaler technique be counteracted?
Extrafine beclometasone; more potent
smaller particles have improved lung deposition, can reach deeper into lung, less likely to be deposited in the mouth
less reliant on good inhaler technique to receive therapeutic dose
179
Who are steroid cards given to?
those who are likely to have sufficient systemic exposure to CS such that they and other HC workers need to be aware of it
generally those on:
- long-term, high dose ICS
- moderate doses plus drugs that inhibit CYP450 e.g. HIV protease inhibitors
- oral CS treatment lasting more than 3 wks
180
Why are steroid cards given?
There is a risk of rebound ie. asthma exacerbations if CS dosing is stopped suddenly
181
How are corticosteroids recommended to be stopped?
should be tapered off gradually as part of step-down system
182
What does the wording of a steroid warning card indicate?
- patient on sufficient steroid dosage
- hypothalamic-pituitary-adrenal axis may be affected
183
What are LTRAs?
leukotriene receptor antagonists (preventers)
184
What receptor do LTRAs block?
cysteinyl leukotriene receptor 1
185
What is the role of the Cysteinyl leukotriene receptor 1 in asthma?
1. mediates bronchial smooth muscle contraction in response to D4 and C4
2. implicated in inflam-induced increased vascular permeability that leads to oedemea and eosinophil chemotaxis
both of these contribute to delayed-phase bronchoconstriction
186
How effective are LTRAs in comparison to ICS in terms of asthma treatment?
- effective at reducing some elements of inflam response
- do not effect freq and severity of attacks as well as ICS
187
Why might LTRAs be less effective than ICS at reducing attack severity and freq?
they have a relatively limited spectrum of anti-inflam activity compared to broad spec effects mediated by ICS
188
LTRAs are particularly helpful in what sorts of patients?
those with atopic tendency ie. allergy driven asthma ;
in particular those with allergic rhinitis
189
What are two examples of LTRAs?
- Montelukast
- Zafirkulast
190
What are the most common side effects associated with LTRAs?
- headaches
- upper-resp infection
- abdominal pain
191
In children treated with LTRAs as an alternative to ICS, what is the most common adverse effect?
hyperactivity
192
How long are patients trialled on LTRAs before stopping if ineffective?
3 months
193
What sorts of neuropsychiatric reactions can patients taking LTRAs experience?
- sleep disturbances
- agitation
- aggressive behaviour
- depression
194
Why is it important to counsel patients and their carers taking LTRAs on possible neuropsychiatric effects?
- such rxns not well known among HC professionals, patients, caregivers
- can speak to a doctor early on, potentially discontinue use
195
When are chromones used clinically in the treatment of asthma?
Why are they used?
mostly as alternative to CS in children
recent review identified that the rate of growth in children using CS is reduced
196
What are the two chromones?
cromoglycate and nedocromil
197
What is the mechanism of action for how chromones mediate their anti-inflam effect?
inhibition of mast cell activation;
reduced release of inflam mediators
198
What could be the reason for chromones being less effective than CS?
chromones have no effect on the pulmonary epithelium which also has a role in triggering inflammatory responses, CS do
199
Why might antibodies be used to treat asthma?
For severe cases which are thought to be CS resistant
200
What is omalizumab?
What is its' mechanism of action?
antibody treatment for severe asthma
targets IgE to prevent binding to Fc receptors on mast cells
therefore preventing cross-linking and reducing degranulation
201
Why is IL-5 thought to be a good target for antibody treatments of asthma?
Why is this significant?
associated with eosinophil recruitment, activation
reduction of eosinophil recruitment is important therapeutic goal to limit airway remodelling and disease progression
202
What are the problems associated with antibody treatments?
1. high costs
2. must be given via injection
3. can trigger immune responses e.g. anaphylaxis
203
What is an example of an antibody treatment that targets IL-5?
Mepolizumab
204
When might patients with mild asthma experience severe symptoms?
respiratory infection e.g. flu
205
What causes severe asthma symptoms when experiencing a respiratory infection?
additive effect of different inflam response as well as that from asthma causes severe symptoms
206
Why do asthma patients experiencing respiratory infections often require an oral course of steroids to resolve inflammation?
patients are less sensitive to CS treatment
207
What characterises inflammation caused by respiratory viral or bacterial infections?
recruitment of neutrophils to the lungs ;
also association between neutrophils and steroid-resistant asthma
208
Which interleukins are considered anti-inflammatory?
IL-1, IL-10, IL-12
209
What are four local side effects of high dose ICS?
1. pneumonia (COPD)
2. dysphonia (hoarseness)
3. oropharyngeal Candidia
4. cough
210
What are some systemic side effects thought to be caused by high dose ICS?
1. adrenal suppression
2. growth suppression
3. bruising
4. osteoporosis
5. cataracts
211
What causes the local side effects of ICS?
deposition of ICS in oropharynx
212
How does the occurrence of dysphonia differ depending on device used?
as common as 50% prevalence in patients using MDI
thought to be reduced in those using dry powder inhalers
213
What is thought to be the cause of dysphonia?
is it reversible?
myopathy of laryngeal muscles
when treatment is withdrawn
214
How can the risk of oropharyngeal Candida be reduced?
use of large volume spacer devices that reduce the dose of ICS that deposits on the oropharynx
215
Why are systemic effects of ICS more common in those using MDI?
- 80-90% of dose deposits in oropharynx, is swallowed
- dose absorbed from GI tract, enters systemic circulation
216
How can systemic effects be reduced in those using dry powder inhalers?
mouth washing and disposing fluid
217
What should patients using a daily dose of more than 800 micrograms of ICS be doing to reduce systemic absorption?
1. using a spacer
2. mouth washing
218
How do CS cause hypothalamic-pituitary-adrenal axis suppression?
by reducing corticotrophin (ACTH) production which reduces cortisol secretion by the adrenal gland
219
How do CS lead to a reduction in bone mass?
1. direct effects on bone formation and resorption
2. indirectly by suppression of HPA and pituitary-gonadal axis
3. effects on intestinal and renal Ca2+ (re)absorption
220
How do oral and topical corticosteroids effect connective tissue?
1. thinning of skin
2. easy bruising
3. telangiectasia - widened venules cause thread-like skin patterns
221
Why do corticosteroids effect connective tissue?
probabaly due to loss of extracellular ground substance within the dermis, due to inhibitory effect on dermal fibroblasts
222
How might asthma effect growth in young patients?
How is this counterbalanced?
- delayed onset of puberty
- decceleration of growth velocity; more pronounced with severe disease
asthmatic children appear to grow for longer
223
Are corticosteroids safe to use when pregnant?
no evidence for adverse effects of ICS on pregnancy, delivery or foetus
224
