0
Q
In the parasympathetic division, which nerve carries preganglionic fibres?
A
Vagus nerve
1
Q
What innervation of the airways is the dominant neuronal control of bronchial smooth muscle tone?
A
Parasympathetic cholinergic innervation
2
Q
In the parasympathetic division, where are the ganglia embedded?
A
In the walls of bronchi and bronchioles
3
Q
What do post-ganglionic fibres of the parasympathetic division do?
A
Innervate bronchial smooth muscle and submucosal glands
4
Q
What 3 things does stimulation of the parasymapthetic division cause?
A
- Bronchial smooth muscle contraction mediated by ACh acting upon M3 muscarinic ACh receptors
- Increased mucus secretion mediated by ACh acting upon M3-muscarinic ACh receptors
- Collectively, increased airway resistance
5
Q
A distinct subpopulation of postganglionic parasympathetic fibres employ vasoactive intestinal peptide (VIP) and nitric oxide (NO) as transmitters - when stimulated what do these do?
A
Relax bronchial smooth muscle
6
Q
What division has no, or sparse innervation of bronchial smooth muscle in humans?
A
Sympathetic division
7
Q
What do postganglionic fibres of the sympathetic division supply?
A
Sub-mucosal glands and smooth muscle of blood vessels
8
Q
What does stimulation of the sympathetic division do to bronchial smooth muscle?
A
Relaxation (via beta-2-adrenoceptors activated by adrenaline released from the adrenal gland)
9
Q
In the sympathetic division: pre-ganglionic fibres release ACh - what does this activate?
A
Nicotinic ACh receptors on adrenal chromaffin cells
10
Q
Sympathetic division: once ACh from pre-ganglionic fibres have been received at nicotinic ACh receptors what is released?
A
Adrenaline (and noradrenaline) into circulation
11
Q
Sympathetic division: once noradrenaline has been released into the circulation what receptors are activated and what occurs?
A
Activation of beta-2-adrenoceptors on bronchial smooth muscle cells by adrenaline causes relaxation.
12
Q
What does stimulation of the sympathetic division do to mucus secretion?
A
Decreases mucus secretion mediated by beta-2-adrenoceptors
13
Q
What does stimulation of the sympathetic division do to mucociliary clearance?
A
Increases it mediated by beta-2-adrenoceptors
14
Q
What is the name for a recurrent and reversible obstruction to teh airways in response to substances which are not necessarily noxious?
A
Asthma
15
Q
Give 4 common causes of asthma attacks
A
- Allergens (in atopic individuals)
- Exercise (cold,dry air)
- Respiratory infections (e.g. viral)
- Smoke, dust, environmental pollutants
16
Q
In asthma what 3 things are caused by intermittent attacks of bronchoconstriction?
A
- Cough
- Wheezing
- Difficulty in breathing
17
Q
What involves pathalogical changes to the bronchioles that result from long standing inflammation?
A
Chronic asthma
18
Q
Give 4 pathological changes caused by chronic asthma
A
- Increased mass of smooth muscle (hyperplasia and hypertrophy)
- Accumulation of intersitial fluid (oedema)
- Increased secretion of mucus
- Epithelial damage (exposing sensory nerve endings)
19
Q
Airway narrowing by inflammation and bronchoconstriction increase airway resistance, what do they decrease?
A
FEV1 and PEFR
20
Q
Name 2 sensory nerve endings exposed by epithlial damage
A
- C-fibres
2. Irritant receptors
21
Q
What contributes to increased sensitivity of the airways to bronchoconstriction influences (and may cause neurogenic inflammation) by the release of various peptides?
A
Epithelial damage
22
Q
What is another term for inhaled bronchoconstrictors?
A
Spasmogens (e.g. histamine or methacholine [muscarinic ACh receptor agonist])
23
Q
What two phases comprise an asthma attack?
A
Immediate - bronchospasm
Delayed - inflammatory reaction
24
When an individual is exposed to an allergen what first step occurs?
Phagocytosis by antigen presenting dendritic cell
25
In a non-atopic individual, after phagocytosis by the dendritic cell what type of response occurs?
Low-level TH1 response
26
What type of response is a cell-mediated immune response involving IgG and macrophages?
Low-level TH1 response
27
In an atopic individual, ocne a dendritic cell has phagocytosed the antigen what response occurs?
Strong TH2 response
28
What is a strong TH2 response?
Antibody-mediated immune response involving IgE
29
What are the two phases in the development of allergic asthma?
Induction phase
| Effector phase
30
In the induction phase of teh development of allergic asthma - what does the antigen presenting cell present the processed antigen to?
CD4 T cell
31
During the induction phase in the development of asthma - what does the CD4 T cell do to TH0 cells?
Causes them to preferentially mature to TH2 cells that produce a cytokine environment
32
During the induction phase in the development of allergic asthma - what do the T helper 2 cells activate and how?
Activate B cells by binding to them and by IL-4 production
33
During the induction phase of the development of allergic asthma - what happens to the B cells?
They mature into IgE secreting plasma cells
34
During the effector phase in the development of allergic asthma - what do the eosinophils differentiate and activate in response to?
IL-5 released from TH2 cells
35
During the effector phase in the development of allergic asthma - what do mast cells in airway tissue express IgE receptors in response to?
IL-4 and IL-13 released from TH2 cells
36
During the development of allergic asthma - what does the subsequent presentation of antigen cross link with?
IgE receptors
37
During the development of asthma - what does subsequent presentation of antigen stimulate?
Calcium entry into mast cells and the release of Ca2+ from intracellular stores
38
During the development of allergic asthma - what does the increase in intracellular calcium cause the release of?
1. Secretory granules containing preformed histamine and the production and release of other agents (e.g. leukotrienes LTC4 and LTD4) that cause airway smooth muscle contraction.
2. Substances (e.g. LTB4 and platelet-activating factor PAF and prostaglandins (PGD2) that attract cells causing inflammation (e..g mononuclear cells and eosinophils) into the area
39
What are chemotaxins and chemokines (LTB4, PAF, PGD2) and spasmogens (histamine, leukotrienes - LTC4, LTD4) released from and what are they released in response to?
Activated mast cell in response to increased intracellular calcium ion levels.
40
During the immediate phase of asthma - what are the first two cells to react?
Mast cells and mononuclear cells
41
During the immediate phase of asthma - what two substances do mast cells release?
Spasmogens (cysLTs and histamine)
| Chemotaxins and chemokines
42
In the late phase of asthma - what do chemotaxins and chemokines released from mast cells do?
Infiltration of cytokines releasing TH2 cells and monocytes, activation of inflammatory cells, particularly eosinophils
43
During the late phase of asthma - what two substances do eosinophils release?
Mediators cysLTs and others
| Eosinophil major basic and catonic proteins
44
In the late phase of asthma - what do the mediators cysLTs and others cause?
Airway inflammation, airway hypersensitivity
| Bronchospasm, wheezing and cough
45
During the late phase of asthma - what do eisoniphil major basic and catonic proteins cause?
Epithelial damage which leads to airway hypersensitivity
46
What two basic classes can drugs used in the treatment of asthma be placed into?
Relievers and controllers/preventors
47
What do relievers act as?
Bronchodilators
48
What do controllers/preventors act as?
Inflamamtory agents that reduce airway inflammation
49
Name 3 types of drugs that act as relievers in asthma
1. Short acting beta-2-adrenoceptor agonists
2. Long acting beta-2-adrenoceptor agonists
3. CysLT receptor antagonists
50
Name 3 groups of drugs that are controllers/preventors
1. Glucocorticoids
2. Chromoglicate
3. Humanised monoclonal IgE antibodies
51
Which group of drugs is both a reliever and a controller/preventor?
Methylxanthines
52
What act as physiological antagonists of all spasmogens?
Beta-2-adrenoceptor agonists
53
When a beta-2-adrenoceptor agonist acts on a beta-2-adrenoceptor on airway smooth muscle, what becomes activated?
Gs which then activates denylyl cylase
54
Once a beta-2-adrenoceptor agonist has acted on a receptor and caused stimulation of Gs and then Adenylyl cylcase, what does adenylyl cyclase then catalyse?
The conversion of ATP to cyclic adenosine monophosphate (cAMP)
55
Once a beta-2-adrenoceptor agonist has acted on a receptor and caused the conversion of ATP to cAMP, what does cAMP then inhibit and stimulate?
Inhibits PDE - 5 AMP
| Stimulates PKA
56
Once a beta-2-adrenoceptor agonist has acted on a receptor andc caused the stimulation of PKA (protein kinase A), what becomes phosphorylated and what is the end result?
Phosphorylation of MLCK (myosin light chain kinase)
| Relaxation of airway smooth muscle
57
In common with most G protein coupled receptors (GPCR), what does persistent activation of beta-2-adrenoceptors cause?
Receptor desensitisation and endocytosis (resulting in loss of function)
58
During over activation of beta-2-adrenoceptors and desensitisation, what two kinases are involved?
1. Protein kinase A (PKA)
| 2. G protein receptor kinases (GPRKs) - specifically beta-adrenoceptor kinases
59
During the desensitisation of beta-2-adrenoceptors, what do protein kinase A and G-protein receptor kinase do to the activated beta-2-adrenoceptor?
Phosphorylate it
60
What can be said about hte phosphorylation of a protein kinase A receptor?
Can be phosphorylated with no agonist bound
61
What can be said about a g-protein receptor kinase receptor in relation to phosphorylation?
Receptor is phosphorylated only when agonist is bound
62
What does a PKA phosphorylated beta-2-adrenoceptor result in?
Reduced G-protein coupling
63
What does a GRK phosphorylated beta-2-adrenoceptor result in?
Formation of beta-arrestin receptor complex which leads to loss of G-protein coupling/endocytosis
64
What acts as a scaffold protein that links the desensitised beta-adrenoceptors to endocytic machinery that internilise the receptor?
Beta-arrestin
65
How are receptors internalised by beta-arrestin?
In clathrin-coated pits and vesicles and trafficked to either endosomes for recycling, or lysosomes for degradation.
66
When does beta-arrestin unbind from the vesicle?
Between endocytosis and the endosomal vesicle
67
In an endosomal vesicle the agonist is still in the receptor on the membrane, when the agonist moves in what occurs to the cell environment?
Turns more acidic (acidic vesicle)
68
Name two short acting beta-2-adrenoceptor agonists
1. Salbutamol
| 2. Albuterol
69
What are the first line treatment for mild, intermittent asthma?
Beta-2-adrenoceptor agonists - short acting
70
How long does it take for a short acting beta-2-adrenoceptor agonists to reach maximal effect and how long does relaxation persist for?
30 minutes
| Persists for 4-6 hours
71
What increases mucus clearance and decreases mediator release from mast cells and neutrophils?
Short acting Beta-2-adrenoceptor agonists
72
Give two adverse effects due to unwanted systemic absorption of inhaled short acting beta-2-adrenoceptor agonists
1. Fine tremor
| 2. Occasional tachycardia
73
Name a long acting beta-2-adrenoceptor agonist?
Salmeterol
74
What type of beta-2-adrenoceptor agonists are useful for nocturnal asthma?
Long acting beta-2-adrenoceptor agonists because of their long half life
75
Can long acting beta-2-adrenoceptor agonists be used as monotherapy?
No
76
What does the use of selective beta-2-adrenoceptor agonists reduce?
Potentially harmful stimulation of cardiac beta-1-adrenoceptors
77
Why are non-selective beta-adrenoceptor antagonists (e.g. propranolol) contraindicated in asthma?
Because the risk of bronchospasm
78
Where do cysLT antagonists act competitively at?
The CysLT receptor
79
Name three CysLTs?
LTC4, LTD4, LTE4
80
Where are cysLTs derived from?
Mast cells
81
When cysLTs infiltrate inflammatory cells what occurs?
Smooth muscle contraction, mucus secretion and oedema
82
During the use of cysLT receptor antagonists, once mast cells have been activated what does phospholipase A2 release?
Intracellular arachidonic acid
83
During cysLT antagonist use, what does arachidonic acid stimulate?
Mast cell 5-lipoxygenase by FLAP
84
What is 5-lipoxygenase blocked by?
Zileuton
85
During cysLT antagonist use, what occurs once mast cell 5-lipoxygenase has been stimulated by FLAP?
LTA4 is produced which in turn creates LTB4 and LTC4
86
During cysLT antagonist drug use, what two substances are transported across the mast cell membrane?
LTB4 and LTC4
87
During cysLT antagonist drug use, what does LTB4 do once it has crossed the mast cell membrane?
Infiltration of inflammatory cells released cysLTs
88
During cysLT receptor mechanisms, once LTC4 has crossed the mast cell membrane, what occurs?
It splits into LTD4 and LTE4 which act on the cysLT receptor (which antagonists block)
89
Once the cysLT receptor has been activated what two responses occur?
1. Bronchoconstriction (early phase)
| 2. Inflammation (delayed phase)
90
Name 2 cysLT receptor antagonists?
Montelukast and Zafirlukast
91
What drugs are effective as add on therapy in mild persistent asthma and in combination with other medications in more severe conditions?
CysLT receptor antagonists such as Montelukast and Zafirlukast
92
What two induced bronchospasms are cysLT receptor antagonists such as montelukast and zafirlukast used for?
Antigen-induced and exercise induced bronchospasm
93
How are cysLT receptor antagonists such as Montelukast and Zafirlukast delivered?
By the oral route
94
Name 2 xanthines?
Theophylline and aminophylline
95
What type of bronchodilators are present in coffee, tea and chocolate beverages?
Xanthines
96
What type of bronchodilators have an uncertain molecular mechanism of action - might involve inhibition of isoforms of phosphodieterases (i.e. PDE III and IV) that inactivate cAMP and cGMP (second messengers that relax smooth muscle and perhaps exert an anti-inflammatory effect)
Xanthines
97
What are second line drugs used in combination with beta-2-adrenoceptor agonists and glucocorticoids?
Xanthines such as theophylline and aminophylline
98
How are xanthines delivered?
Oral route as sustained release preperations
99
Give 4 adverse effects of xanthines at therapeutic concentrations?
1. Nausea
2. Vomiting
3. AAbdominal discomfort
4. Headache
100
Name a drug used in the treatment of asthma that is an anti-inflammatory agent?
Corticosteroids
101
The adrenal cortex synthesises two major classes of steroid hormone that are released into the circulation - what are they?
1. Glucocorticoids
| 2. Mineralcorticoids
102
What part of the adrenal cortex are glucocorticoids produced in?
Zona fasiciculata
103
What part of the adrenal cortex are mineral corticoids produced in?
Zona glomerulosa
104
What glucocorticoid is the main hormone in man?
Cortisol
105
What hormone decreases inflammatory responses, decreases immunological responses, increases liver glycogen deposition, increases gluconeogenesis, increases glucose output from liver, decreases glucose utilisation, increases protein catabolism, increases bone catabolism and increases gastric acid and pepsin secretion?
Hydrocortisone
106
Name a mineralcorticoid?
Aldosterone
107
What does aldosterone regulate?
The retention of salt and water by the kidneys
108
Are mineralcorticoids wanted in the treatment of inflammatory conditions?
No
109
Name a synthetic derivative of cortisol
Beclametasone
110
What have no direct bronchodilator action and are ineffective in relieving bronchospasm when given acutely?
Glucocorticoids
111
What are the mainstay of treatment in the prohpylaxis of asthma and are preferably delivered by the inhalational route to minimise adverse systemic effects?
Glucocorticoids
112
What do glucocorticoids signal via?
Nuclear receptors (class 1), specifically GRalpha
113
How do glucocorticoids enter cells and what type of molecules are they?
Diffusion across plasma membranr
| Lipophilic molecules
114
Within the cytoplasm - what do glucocorticoids combine with?
GRalpha
115
Once the glucocorticoid has combined with GRalpha in the cytoplasm - what does this produce?
Inhibitory heat shock proteins (e.g. HSP90)
116
Once the glucocorticoid has combined with the GRalpha receptor where does the activated receptor translocate to?
The nucleus aided by importins
117
Within the nucleus - what does the activated GRalpha receptor that is combined with a glucocorticoid monomers assemble into?
Homodimers
118
Within the nucleus, what do activated GRalpha receptor homodimers bind to?
Glucocorticoid response elements (GRE) in the promoter region of specific genes
119
Molecular mechanism of action of glucocorticoids: once the nucleus activated receptor homodimer has binded to GRE what happens to transcription?
Transcription of specific genes is either switched on (transactivated) ot switched off (translpressed) to alter mRNA levels and the rate of synthesis of mediator proteins.
120
What are regulated by glucocorticoids acting at glucocorticoid response elements, or by modifying the structure of chromatoin via deacetylation of histones?
Genes
121
Generally, what do glucocorticoids do to the transcription of genes encoding anti-inflammatory proteins?
Increase transcription
122
What do glucocorticoids do the the transcription of genes encoding inflammatory proteins?
Decrease transcription
123
What is expression of inflammatory genes associated with?
Acetylation of histones by histone acetyltransferases (HATs)
124
What unwinds DNA from histones allowing transcription?
Acetylation
125
What do glucocroticoids recruit to activated genes to switch off gene transcription?
Histone deacetylases (HDACs)
126
What is a simple definition of chromatin?
DNA plus histones
127
What part of bronchial asthma are glucocorticoids particularly relevant to?
Inflammation
128
What prevents allergen-induced influx into lung and cause apoptosis of eosinophils?
Glucocortiocids
129
What do glucocorticoids decrease the formation of?
TH2 cytokines and cause apoptosis of TH2 cells
130
What do glucocorticoids reduce the number of and decrease?
```
Number of mast cells
Decrease Fc (IgE receptor) expression
```
131
What do glucocorticodis produce the production of?
IgE antibodies
132
What effect does glucocorticpdis have on eosinophils?
Reduce numbers by apoptosis
133
What effect does glucocorticodis have on T-lymphocytes?
Reduce cytokines
134
What effect does glucocorticoid have on mast cells?
Reduce numbers
135
What effect does glucocorticoids have on Macrophages?
Decrease cytokines
136
What effect do glucocorticoids have on dendritic cells?
Reduce numbers
137
What do corticosteroids/glucocorticoids do to epithelial cells?
Reduce cytokines and mediators
138
What do corticosteroids do to endothelial cells?
Decrease leak
139
What do corticosteroids/glucocorticoids do to airway smooth muscle?
Increase beta-2-receptors and decrease cytokines
140
What do glucocorticoids/corticosteroids do to mucus glands?
Decrease mucus secretion
141
What combined with glucocorticoids give effective long term treatment of asthma?>
Long-acting beta-2-adrenoceptor agonist (LABA)
142
In mild/moderate asthma - how is beclametasone (glucocorticoid) given?
Inhalation from a metered dose inhaler
143
Name 2 adverse effects of glucocorticoids (beclametasone), due to deposition of steroid in the oropharynx?
```
Dysphonia (hoarse and weak voice)
Oropharyngeal candidiasis (thrush)
```
144
In chronic, severe, or rapidly deteriorating asthma - what may be used in combination with an inhaled corticosteroid to reduce the oral dose required and minimise unwanted systemic effects?
Prednisolone
145
What type of drugs are second line drugs and now infrequently used, however can be used prophylactically in the treatment of allergic asthma in children?
Cromolins
146
What drugs are often described as mast cell stablisers?
Cromolins
147
Do cromolins have a direct effect on bronchial smooth muscle?
No
148
What drugs have an uncertain molecular mechanism of action that incldues a weak anti-inflamamtory effect. A decrease in the sensitivity of irritant receptors associated with sensory C-fibres that trigger exaggerated reflexes and reduction of cytokine release are potential mechanisms?
Cromolins
149
Name a specific cromolin agent?
Sodium cromoglicate
150
How is sodium cromoglicate delivered?
By inhalation
151
What drug can reduce both phases of an asthma attack, but efficacy may take several weeks to develop - requires frequent dosing?
Sodium cromoglicate
152
What are recent approaches to the treatment of asthma that involve anti-inflammatory actions?
Monoclonal antibodies directed against IgE
153
Name a monoclonal antibody direcetd against IgE?
Omalizumab
154
What drug binds IgE via Fc to prevent attachment to Fc receptors - suppresses mast cell response to allergens?
Omalizumab
155
What does omalizumab reduce on various inflammatory cells?
The expression of Fc receptors
156
How is omalizumab or other monoclonal antibodies directed against IgE delivered?
Intravenously and is expensive
157
What is characterised by airflow reduction that is in some patients partially reversible (with bronchodilators) but which progressively worsens (as assessed by FEV1) and by exacerbation of symptoms including cough and mucus production?
COPD
158
What can COPD be clinically divided into\?
Emphysema and bronchitis
159
What does smoking/air pollution stimulate?
Resident alveolar macrophages
160
In COPD, once resident alveolar macrophages have been stimulated - what is produced?
Cytokines
161
In COPD, once resident alveolar macrophages have stimulated cytokine production - what occurs?
Activation of neutrophils, CD8 T cells and increased macrophage numbers
162
In COPD, what do the activation of neutrophils, CD8 T cells and increased macrophage numbers release?
Matrix metalloproteinases (e.g. elastase) and free radicals
163
What type of COPD gives inflammation of the bronci and bronchioles, cough, ckear mucoid sputum, indections with purulent sputum and increasing breathlessness?
Chronic bronchitis
164
Which type of COPD has distension and damage to alveoli and the destruction of acinial pouching in alveolal sacs?
Emphysema
165
What three types of muscarinic acetylcholine receptors do human airways express?
M1, M2 and M3
166
Where is receptor M1, what does it facilitate?
Ganglia
| Faciliates transmission mediated by ACh acting on Nicotinic receptors (nAChR)
167
Where is receptor M2 and what does it act as?
Post ganglionic neurone terminals
| Acts as inhibitory autoreceptors reducing the release of ACh
168
Where is receptor M3 located and what does it mediate?
Smooth muscle
| Mediates contraction to ACh (also present on mucus secreting cells evoking increased secretion)
169
What is a corner stone of the treatment of COPD?
Reducing parasympathetic activity with muscarinic receptor antagonists
170
What act as pharmacological antagonists of bronchoconstriction caused by smooth muscle M3 receptor activation in response to ACh released from parasympathetic fibres (and non-neural cells also)?
Muscarinic acetylcholine receptor antagonists
171
Molecular mechanism of airway smooth muscle contraction: what is activation by ACh blocked by?
Muscarinic receptor antagonists
172
Molecular mechanism of airway smooth muscle contraction: What does M3 muscarinic receptor stimulate?
Gq/11
173
Molecualr mechanism of airway smooth muscle contraction: what does Gq/11 in smooth muscle stimulate?
PLC - Phospholipase C
174
Molecular mechanisms of airway smooth muscle contraction: what does phospholipase C PLC do?
Converts PIP2 to IP3 (Phosphatidylinositol bisphosphate to inositol triphsophate)
175
Molecular mechanism of airway smooth muscle contraction: what does IP3 stimulate?
Ca2+ release from SR (sarcoplasmic reticulum)
176
Molecular mechaism of airway smooth muscle contraction: what does Ca2+ release from sarcoplasmic reticulum finally lead to?
Contraction of airway smooth muscle
177
Name 2 short acting muscarinic antagonists (SAMAs)
1. Ipratropium
| 2. Oxitropium
178
Name 2 long acting muscarinic antagonists (LAMAs)
1. Tiotropium
| 2. Aclidinium
179
How are all competitive muscarinic receptor antagonists given (SAMAs and LAMAs)?
Inhalation
180
What does the quaternary ammonium group c.f. atropine) in muscarinic receptor antagonists do?
Reduces absorption and systemic exposure avoiding multiple potential adverse affects
181
What type of amine is found in atropine?
Tertiary amine
182
How long does it take for muscarinic ACh receptor antagonists to take action?
>30 minutes (aclinidium may be faster)
183
What do muscarinic ACh receptor antagonists do?
Relax bronchospasm caused by irritant stimuli (irritants initiate a vagal reflex that liberates ACh) and also basal block ACh mediated basal tone
184
What do muscarinic ACh receptor antagonists do to mucus secretion?
Decrease it
185
What muscarinic ACh receptor antagonist is a non-selective blocker of M1, M2 and M3 receptors?
Ipratropium
186
Which msucarinic ACh receptor antagonist blocks M3?
Tiotropium
187
How is the functional selectivity of tiotropium over ipratropium achieved?
By its longer half-life at the M3 muscarinic receptor
188
Why does tiotropium not block M2?
Because the relase of ACh from parasympathetic post-ganglionic neurones is increased
189
What is a prejunctional inhibitory autoreceptor (activatin by ACh inhibits further ACh release, non-selective antagonists increase release) found on hte post-ganglionic neurone?
M2
190
What short acting, and two long acting beta-2-adrenoceptor agonists are used in the treatment of COPD?
Salbutamol
| Salmeterol and formoterol
191
What is the name of a recently licensed ultra-LABA with a rapid onset of action with once daily dosing?
Indacaterol
192
What is superior to either drug alone in increasing FEV1 in moderate COPD?
A combination of LABA and LAMA (salmeterol/tiotropium)
193
What is the prominent PDE expressed in neutrophils, T cells and macrophages?
Phosphodiesterase-4 (PDE4)
194
What is Rofumilast?
A selective PDE4 inhibitor
195
What drug suppresses inflammation and emphysema in animal models of COPD. Approved as oral treatment for severe COPD accompanied by chronic bronchitis but has limiting adverse GI effects?
Rofumilast
196
Why might glucocorticoids be unresponsive in COPD patients?
Due to oxidative/nitrative stress (associated with chronic inhalation of tobacco smoke) - HDAC2 is reduced in COPD
197
What is a common and often debilitating disease involving acute, or chronic, inflammation of the nasal mucosa?
Rhinitis
198
What is rhinorrohea?
Runny nose - watery mucus accumulation in nasal cavity
199
What is nasal congestion and obstruction in rhinitis caused by?
Swelling of nasal mucosa largely due to dilated blood vessels - particularly cavernous sinusoids
200
What are sneezing, itching, nasal congestion and rhinorrohea all features of?
Rhinitis
201
What are the three types of rhinitis?
1. Allergic
2. Non-allergic
3. Mixed
202
What are the three types of allergic rhinitis?
1. Seasonal (SAR)
2. Perennial (PAR)
3. Episodic
203
During allergic rhinitis - what does inhalation of allergen increase?
Specific IgE levels
204
During allergic rhinitis: once inhalation of an allergen has increased specific IgE levels, what does IgE bind to?
Receptors on mast cells and basophils
205
During allergic rhinitis - what does re-exposure to allergen cause, in relation to cells?
Mast cell and basophil degranulation
206
During allergic rhinitis: what does degranulation of mast cells and basophils cause?
Release of mediators including histamine, cysLTs, tryptase, prostaglandins, causing acute itching, sneexing, rhinorrhoea and nasal congestion
207
During allergic rhinitis: what does the delayed response caused by recruitment of lymphocytes and eosinophils to nasal mucosa contribute to?
Congestion and obstruction
208
What does non-allergic rhinitis refer to?
Any rhinitis, acute or chronic that does not involve IgE - dependent events - caused are diverse
209
What are 5 causes of non-allergic rhinitis?
1. Infection - infectious rhinitis (largely viral)
2. Hormonal imbalance - hormonla rhinitis (e.g. pregnancy)
3. Vasomotor disturbances - vasomotor rhinitis (idiopathic)
4. Nonallergic rhinitis with eosinophilia syndrome (NARES)
5. Medications - drug induced rhinitis
210
What do both rhinitis and rhinorroea involve?
Increased mucosal blood flow, increased blood vessel permeability, or both - these increase he volume of the nasal mucosa and cause difficulty breathing in
211
Targets in the treatment of rhinitis and rhinorrhoea: what is the treatment for anti-inflammatory effects?
Glucocorticoids
212
Targets in the treatment of rhinitis and rhinorrhoea: what is the treatment for mediator receptor blockade?
H1 receptor antagonists
| cysLT receptor antagonists
213
Targets in the treatment of rhinitis and rhinorrhoea: what is the treatment for Nasal blood flow?
Vasoconstrictors
214
Targets in the treatment of rhinitis and rhinorrhoea: what is the treatment for antiallergic effects?
Sodium chromoglicate
215
Do glucocorticoids reduce vascular permeability?
Yes
216
What is the mainstay therapy for seasonal allergic rhinitis and perrennial allergic rhinitis and are of value in NARES and vasomotor rhinitis?
Glucocorticoids
217
How are glucocorticoids for rhinitis administered?
Topically as a spray to the nasal mucosa (i.e. intranasal administration)
218
Are glucocorticoids for rhinitis effective as monotherapy?
Yes
219
What might glucocorticodis be combined with in moderte-to-severe rhinitis?
Anti-histamines
220
Give three examples of glucocorticodis used in rhinitis
1. Beclametasone
2. Fluticasone
3. Prednisolone (oral)
221
What are anti-histamines?
H1 receptor antagonists
222
What is the mechaism for anti-histamines (H1 receptor antagonists)?
Competetive antagonists of H1 receptors reduce effects of mast cell derived histamine
223
Give three effects of mast cell derived histamine?
1. Vasodilatation and increased capillary permeability
2. Activation of sensory nerves
3. Mucus secretion from submucosal glands
224
What drugs are effective in SAR, PAR and episodic allergic rhinitis but less so for non-allergic rhinitis?
Anti-histamines
225
How are anti-histamines for rhinitis administered?
Orally, or as an intranasal spray (azelastine)
226
Are anti-histamines effective as monotherapy?
Yes
227
Anti-histamines are available as first and second generation agents - which is preferred and why?
```
Second generation
Reduced sedation (do not cross blood brain barrier) and lack of anti-cholinergic effects
```
228
Give three examples of second generation anti-histamines
1. Loratidine
2. Fexofenadine
3. Cetirizine (also has mild anti-inflammatory action)
229
What are anti-cholinergic drugs?
Muscarinic receptor antagonists
230
What is the mechanism for anti-cholinergic drugs (muscarinic receptor antagonists)?
ACh released from post-ganglionic parasympathetic fibres activates muscarinic receptors on nasal glands causing a watery secretion that contributes to rhinorrhoea - blocked by muscarinic antagonists
231
What drugs are effective in reducing rhinorrhoea in PAR and SAR but have no influence upon itching, sneezing and congestion?
Anti-cholinergic drugs (note the anti-cholnergic activity of first generation H1 blockers may contribute to their ability to suppress rhinorrhoea)
232
How are anti-cholinergic drugs administered?
By the nasal route
233
Give one adverse effect of anti-cholinergic drugs
May cause dryness of nasal membranes
234
Name the single sole agent used in the anti-cholinergic drug class?
Ipratropium
235
Give the mechanism for sodium chomoglicate?
Purportedly mast cell stabilsation, but this is uncertain
236
What drug is used for maintanence treatment of allergic rhinitis with an onset of action of 4 to 7 days, but weeks may be required for full effect?
Sodium chomoglicate
237
Give the mechanism for Cysteinyl Leukotriene Receptor Antagonists
CysLT receptor antagonists reduce the effects of cysLTs upon the nasal mucosa
238
Which drugs are equi-effective with H1 receptor antagonisys in treating PAR and SAR with which their effect may be additive?
CysLT receptor antagonists
239
How are cysLT receptor antagonists administered?
By the oral route
240
Name the sole agent used in the class of cysLT receptor antagonists?
Montelukast
241
Which drugs have a mechanism of action that is direct, or indirect, sympathomimetics to mimic the effect of noradrenaline. Produce vasoconstriction via activation of alpha-1-adrenoceptors to decrease swelling in vascular mucosa?
Vasoconstrictors
242
Name a selective alpha-1-adrenoceptor agonisy (given intranasally), which is effective, short term, in reducing congestion in allergic rhinitis?
Oxymetazoline
243
Why is nasal administration of oxymetazxoline for more than a few days not recommended?
Due to the development of a rebound increase in nasal congestion upon discontinuation (rhinitis medicamentosa). Occurs due to receptor desensitisation and down regulation.
JL Respiratory
flashcards
Decks in class (27)
# Cards
-
Physiology204
-
Anatomy108
-
Buzzwords47
-
Glossary51
-
Pharmacology244
-
Histology47
-
Embryology17
-
Tuberculosis41
-
Immunology457
-
Biochemistry67
-
Obstructive Airway Overview46
-
Pulmonary Pathology16
-
Pulmonary Function Tests36
-
Airway Therapeutics Overview67
-
Bronchial Carcinoma86
-
Respiratory Tract Infection62
-
Chronic Pulmonary Infection50
-
Restrictive Lung Diseases Overview48
-
Interstitial and Occupational Lung Disease71
-
Pulmonary Vascular Disease Overview49
-
Pulmonary vascular disease and pleural disease40
-
Stridor and Sleep Apnoea26
-
Respiratory Disease in Childhood35
-
Clinical Signs22
-
CCP1
-
Microbiology34
-
Cystic Fibrosis28
