Pharmacology Flashcards
1
Q
What does the stimulation of postganglionic cholinergic neurones cause?
A
- Bronchial smooth muscle contraction (M3 receptors)
- Increased mucus secretion (M3 receptors on goblet cells)
2
Q
What does the stimulation of postganglionic parasympathetic non-cholinergic neurones cause?
A
Stimulation of postganglionic parasympathetic neurons typically causes constriction of the airways.
This is why anticholinergic medications, which block the muscarinic receptors, are often used to treat asthma and other respiratory conditions that involve airway constriction.
3
Q
In which four ways does the sympathetic system affect the airways?
A
- Bronchial smooth muscle
- Mucous secretion
- Mucociliary clearance
- Vascular smooth muscle contraction
4
Q
Bronchial smooth muscle is not innervated by sympathetic neurones - how does the sympathetic system influence the bronchi?
A
There is no postganglionic neurone, so innervation of the adrenal gland allows it to act as this neurone, by releasing adrenaline which can cause bronchial smooth muscle by binding to B2 adrenoceptors
5
Q
What are the receptors associated with the sympathetic system in submucosal glands and what is their activated effect?
A
B2 adrenoceptors (act on goblet cells and epithelium) Reduces mucus secretion and increases clearance (mucociliary elevator)
6
Q
Which receptor mediated vascular smooth muscle contraction?
A
alpha1 adrenoceptors
7
Q
What is the sarcoplasmic reticulum?
A
Type of endoplasmic reticulum that regulates calcium ion concentration in skeletal muscle
8
Q
During motor neurone conduction in skeletal muscle, what type of receptor is activated after hormone or neurotransmitter release?
A
G protein coupled receptor (Gq and phospholipase)
9
Q
How is IP3 produced during skeletal muscle contraction?
A
Produced from PIP2 (phosphatidylinositol (4,5) biphosphate after Gq subunit binds to phospholipase
10
Q
What is the function of IP3 in skeletal muscle contraction?
A
Produced IP3 acts as a substrate for the IP3 receptor (transmembrane) which, when bound, allows efflux of calcium ions out of the sarcoplasmic reticulum and into the cytoplasm. Contraction is now viable
11
Q
Describe how calcium can aid the pathway of smooth muscle contraction
A
When the impulse arrives, voltage gated calcium channels open calcium an influx of calcium into the cytoplasm. Calcium can then activate ryodine receptors (calcium activated channels). This allows for calcium efflux out of the sarcoplasmic reticulum
12
Q
Which two main things must be available for muscle contraction to occur?
A
- ATP
- Calcium
13
Q
Why is calcium required for muscle contraction?
A
Calcium combines with calmodulin which creates a complex that activates MLCK
14
Q
What does activated MLCK allow for?
A
Activated MLCK breaks down ATP allowing inactive myosin cross-bridges to enter the cocked position and able to bind with actin filaments
15
Q
What causes smooth muscle relaxation?
A
Dephosphorylation of myosin light chain (MLC) by MLC phosphotase
16
Q
When levels of calcium are high in smooth muscle cells, the rate of phosphorylation will be much higher than dephosphorylation, so for relaxation to occur, what must happen to the levels of calcium
A
They must reduce
17
Q
What effect does adrenaline have when binding to B2 adrenoceptors in smooth muscle?
A
- G protein couples receptor activated (Gs)
- Complex activates adenylyl cyclase which boots cAMP levels
- cAMP combines to PKA
- PKA facilitates smooth muscle relaxation
18
Q
In what 2 ways does PKA stimulate smooth muscle relaxation?
A
- Phosphorylating and inhibting MLCK which inhibits contraction
- Phosphorylating and stimulating myosin phosphotase which facilitates relaxation
19
Q
Chronic asthma can have many negative effects, what are some of these?
A
- Increase in smooth muscle reducing bronchiole diameter
- Inflammation causes build up of oedema
- Increased mucus secretion into lungs causes partial obstruction
- Epithelial lining becomes damaged and cells are shed which exposes sensory nerve endings causing irritability
- Sub-epithelial fibrosis - epithelial cells deposit excess collagen reducing space further in airways
20
Q
What causes bronchial hyper-responsiveness in asthma?
A
Epithelial damage leads to C-fibre (irritation receptor) exposure causing increased sensitivity to bronchoconstrictor influences
21
Q
As a result of epithelial damage in asthma, neurogenic inflammation occurs - what are the cosequences of this?
A
Various peptides are released from these nerve endings
22
Q
Which two components contribute to the severity of asthma?
A
- Hyper-sensitivity - concentration of bronchoconstrictor influences that will evoke asthmatic response
- Hyper-reactivity - The severity of the response experienced
23
Q
What composes the immediate reaction in an asthma attack?
A
Initial bronchospasm and acute inflammation
24
Q
What composes the delayed reaction of asthma?
A
Continued bronchospasm and delayed inflammation.
continued bronchospasm, which is the constriction of the airways due to the contraction of smooth muscle cells in the bronchioles. This can further worsen symptoms such as wheezing, shortness of breath, and coughing.
25
Due to the two phases to an asthma attack, the FEV1 changes over time, but in what ways?
FEV1 - decreases after initial reaction (immediate)
FEV1 - recovers after the immediate reaction
FEV1 - deteriorates again during delayed reaction
FEV1 - recovers fully
26
How does atopic asthma differ from non-atopic asthma in relation to immune system activation?
Non-atopic - low-level immune response TH1 response which mediates IgG and macrophages
Atopic - strong TH2 response that is an antibody mediated immune response involving IgE
27
What are TH0 cells?
Precursors
They differentiate to either TH1 or TH2 cells
28
In the development of allergic asthma describe the induction phase
1. Allergen recognition: An allergen is recognized by antigen-presenting cells (APCs), such as dendritic cells or macrophages, which phagocytose or endocytose the allergen and present it on their MHC-II molecules.
2. Th2 cell activation: APCs present the allergen to Th2 cells, which recognize it through their TCR and release cytokines such as IL-4 and IL-5.
3. IgE production: IL-4 induces plasma cells to produce specific IgE antibodies against the allergen.
4. Mast cell activation: IgE antibodies bind to FcεR1 receptors on mast cells, leading to their degranulation and release of histamines and leukotrienes.
5. Eosinophil activation: IL-5 activates eosinophils, which release leukotrienes and proteases that can cause tissue damage to the respiratory tract if released chronically.
Overall, the induction phase of allergic asthma involves the activation of various immune cells and the production of IgE antibodies that can bind to mast cells and trigger their degranulation, leading to airway inflammation and hyperresponsiveness.
29
In the development of allergic asthma describe the effector phase
* Plasma cells secrete IgE antibodies due to interleukin 4 action
* Interleukin 5 is released from TH2 cells which activates eosinophils
* Mast cells express IgE receptors and become activated due to release of IL-4 and IL-13
30
What are the two phases to the development of allergic asthma?
1. Induction phase
2. Effector phase
31
How do mast cells become activated in allergic asthma?
Antigens combine with IgE antibodies on the surface of mast cells
32
What happens during mast cell activation in allergic asthma?
Calcium enters via calcium channels and it is released from intracellular stores
* Mast cell secrete histamine, leukotrienes (LTC4, LTD4) - causes contraction of airways
* Mast cells release substances (chemokines/chemotaxins) that attract inflammation causing cells to the area
This explains the primary and secondary responses to an asthma attack
The repeated exposure also leads to the recruitment of more inflammatory cells, such as eosinophils, which can cause further damage to the airways.
33
What happens when mast cells release chemotaxins and chemokines during allergic asthma?
* TH2 cells infiltrate the area with monocytes (TH1 may also be involved)
* Inflammatory cells such as eosinophils become activated
* Eosinophils cause damage to epithelium
34
What are the two main types of drugs are used in asthm anad which drug classes are used for each?
Relievers - bronchodilators
* SABAs
* LABAs
* CysLT1 receptor antagonists
Controllers/preventors - anti-inflammatory
* Glucocorticoids
* Cromoglicate
* Humanised monoclonal IgE antibodies
35
Why are LABAs never given as monotherapy?
Monotherapy of LABAs can be harmful
Receptors can lose sensitivity and pharmacological effect over time decreases
This can cause a long-term decrease in the amount of B2 adrenoceptors as they are withdrawn from the surface of cells and potentially broken down by lysomes
36
During stage 3 of asthma treatment, what happens if there is no response to the added LABA?
Dose of ICS is increased
And, if required trial of other therapies such as a CysLT1 receptr antagonist or theophylline is used
37
What are the three classes of B2-adrenoceptor agonists?
1. SABAs
2. LABAs
3. Ultra LABAs
38
Why are SABAs administered by inhalation?
This reduces the dose required and therefore the systemic effects experienced
39
What are some of the potential side effects to SABAs?
* Tachycardia
* Cardiac dysrhythmias
* Hypokalaemia
40
What 3 things do SABAs achieve?
* Bronchodilatation
* Increased mucus clearance
* Decreased mediator release of mast cells and monocytes
41
LABAs are always co-administered with a \_\_\_\_\_\_\_\_\_\_\_\_\_\_
Glucocorticoid
42
What is the benefit that LABAs have over SABAs?
They can be used for nocturnal asthma
but the main benefit of LABA is their longer duration of action
43
What is isoprenaline and why is it not frequently used?
It is a non-selective beta agonist (works on both B1 and B2 adrenoceptors)
It will stimulate cardiac muscle as well as causing bronchodilatation
Selective B2 agonists are preferred for bronchodilation
44
Name a non-selective B arencoceptor agonist
Isoprenaline
45
Why is the use of propranolol dangerous in patients requiring bronchodilation therapy?
Propranolol is a non-selective B adrenoceptor antagonist
It blocks both B1 and B2 adrenoceptors
Adrenaline is required to bind to B2 adrenoceptors in the airways to ensure a relatively relaxed state is maintained
Upon propranolol administration, this cannot occur and there is a risk of bronchospasm
46
What happens when phospholipase A2 acts on activated mast cells?
Intracellular release of arachidonic acid occurs
47
After arachidonic acid is released intracellularly in mast cells, what happens when the mast cells are stimulated by 5-lipooxygenase (FLAP)
Arachidonic acid is metabolised to leukotriene A4 (LTA4) and then subsequently into LTB4 and LTC4which are both secreted into the extracellular spaceby transport proteins
48
LTB4 has what effects in the airways?
Causes infiltration of other inflammatory cells causing the production and release of other leukotrienes including CysLT1 (cysteinyl leukotriene)
LTB4 will also act as a chemokine attracting this leukotriene into the airway cells
49
What happens in the airways to LTC4?
It is metabolised to LTD4 and LTE4
| (LTD4 can also metabolise to LTE4)
50
Whick leukotrienes will act on the CysLT1 receptor?
* LTD4
* LTE4
* CysLT1
51
Activation of the CysLT1 receptor will lead to what?
Contraction of bronchial smooth muscle. , increased vascular permeability, and mucus secretion.
| (and later, inflammation)
52
In the USA, which drug is used to block stimulation is mast cells by 5-lipooxygenase?
Zileuton
53
What are two of the main CysLT1 antagonists?
* Montelukast
* Zafirlukast
54
Why are CysLT1 receptor antagonistsnot are not recommended for relief of severe acute asthma?
The main reason for this is that CysLT1 receptor antagonists have a slower onset of action compared to fast-acting bronchodilators such as salbutamol.
The bronchodilator activity of CysLT1 receptor antagonists is less than salbutamol, and they are not effective against all types of bronchoconstriction stimuli.
Therefore,
they cannot provide immediate relief of symptoms during a severe acute asthma attack.
They are not effective against all contractile stimuli
Salcutamol is effective against any provoking stimulus sue to acting in a physiological manner - cAMP pathway
55
How are CysLT1 receptor antagonists administered?
Orally
56
What are the two main methylxanthines?
1. Theophylline
2. Aminophylline
57
What are the two main actions methylxanthines take to counteract asthma symptoms?
* Bronchodilator action
* Anti-inflammatory action
58
Describe the bronchodilator action of methylxanthines
Normally cAMP is broken down to 5'AMP by phosphodiesterase enzymes
This prevents smooth muscle relaxation
Methylxanthines (at high doses) inhibit phosphodiesterase (3/4) and allow for smooth muscle relaxation
Levels of cAMP can activate protein kinase A which can phosphorylate and inhibit MLCK, or phosphorylate and stimulate myosin phosphotase - preventing contraction/allowing for relaxation
59
How is diaphragmatic contractility affected by the use of methylxanthines?
It is increased
This can reduce fatigue and improve ventilation
60
Describe the anti-inflammatory action of methylxanthines
At high doses, pro-inflammatory mediator release from mast cells is inhibited and mucociliary clearance is reduced
Methylxanthine can induce intra-cellular effects - they can activate histone deacetylase (HDAC) in the nucleus
HDAC removes acetyl groups (in histone proteins), increasing the +ve charge of histone tails and increasing bond strength between histones and DNA.
This means transcription of inflammatory genes occurs less frequently
61
Why does HDAC increase the strength of bonds between histones and the DNA backbone?
Normally acetylation occurs in histone proteins converting amines to amides which neutralises +ve charges
This reduces the amount of +ve charges from the histone proteins bonded to the -ve DNA backbone
This weakens the attraction and promotes the transcription of genes (inflammatory in the case of pharacology) as chromatin expands
HDAC prevents this acetylation occuring ensuring strong bonds remain between histones and DNA
62
Why are methylxanthines not high on the list for the treatment of asthma?
They have serious side effects and very narrow therapeutic window
* Seizures
* Hypotension, dysrhthmias
* GI tract issues - vomiting, discomfort
* Kidney problems
63
How can methylxanthines negatively impact drug metabolism?
They can interfere with enzymes involved in drug metabolism such as the cytochrome P450s
64
What is the adrenal cortex?
The outer layer of the adrenal gland
65
Name the layers of the adrenal corex from most superficial to deep
1. Glomerulosa
2. Fasciculata
3. Reticularis
66
The different layers of the adrenal cortex can synthesise different \_\_\_\_\_\_\_\_\_
Steroids
67
The adrenal cortex synthesises which two major classes of steroid hormone?
1. Glucocorticoids - synthesised in zona fasiciculata
2. Mineralocorticoids - synthesised in zona glomerulosa
68
Are steroid hormones pre-sotred in vasicles or are they synthesised on demand by hormones from the anterior pituitary?
Synthesised on demand by the anterior pituitary gland
69
What is the main glucocorticosteriod produced in humans?
Cortisol
70
What is the main mineralocorticoid in humans and what are its main effects?
Aldosterone
Regulates the retention of water and salt by the kidneys
71
Of the two, which are more useful for asthma treatment, corticosteroids or mineralocorticoids, and why?
Corticosteroids
They have anti inflammatory action and they dampen down the immunological response
72
In basic terms, how is cortisol synthetically altered to allow it to be a suitable asthma treatment?
Cortisol has both corticoid and mineralocorticoid properties
The mineralocorticoid properties are edited out so only the corticoid properties have influence
73
Give three examples of glucocorticosteroids that are synthetic derivatives of cortisol
1. Beclometasone
2. Budesonide
3. Fluticasone
74
Why should glucocorticoids never be administered alone?
They have no (direct) effect on bronchospasm and will not relieve it
75
Why should glucocorticoids be administered by inhalation?
To avoid systemic effects
76
Where are glucocorticoid receptors in cells?
Cytoplasm (or nucleus)
(activation leads to effects in nucleus)
77
How do glucocorticoids enter the nucleus?
By diffusion into the cytoplasm
(they are hydrophobic agents - so thier receptor will be intra-cellular)
78
What is the glucocorticoid receptor called?
GRα
79
The GRα receptor is normally bound to by _____ \_\_\_\_\_\_ \_\_\_\_\_\_\_\_\_\_, specifically \_\_\_\_\_and when the glucocorticoid binds to the receptor _________ will dissociate
Heat shock proteins
HSP90
HSP90
80
Upon glucocorticoid binding to GRα, what occurs initially?
The receptor/agonist complex can move to the nucleus aided by specific karyopherins called importins
81
What happens, initially, when the agonist/receptor complex (glucocorticoid/GRα) reaches the nucleus?
The receptors (whilst bound to glucocorticoids) pair up forming homodimers
82
What does the creation of (GRα receptor) homodimers in the nucleus allow for?
1. Transactivation - transcription of specific genes is switched on
2. Transrepression - transcription of specific genes is switched off
83
Where do the GRα homodimers bind?
Glucocorticoid response elements (GREs)
(in the promotor region of certain genes)
84
Binding of GRα homodimers to glucocoticoid response elements will result in what?
1. Transactivation
2. Transrepression
mRNA levels are altered which alters the level of protein synthesis that occurs and therefore the amount of protein expression
85
Glucocorticoids can influence the type and amount of protein transcribed. Which types of genes will be preferentially transcribed and which will not be?
* Anti-inflammatory genes - transactivated
* Inflammatory genes - transrepressed
Anti-inflammatory genes will be transcribed more and anti-nflammatory proteins will begin to predominate
86
What is chromatin?
The state of histone proteins and DNA being tightly bound together
87
Activated TH2 cells affect B cells in what way?
They induce maturation and clonal expansion of B cells with become plasma cells
This is due to the release of IL-4 from helper T cells
88
How can glucocorticoids affect the actions of TH2 cells?
They suppress the release of IL-4 and IL-5
They also cause apoptosis in TH2 cells
(this suppression indirecetly supresses B cells)
89
Indirect inhibition of B cells by glucocorticoids affects IgE antibody levels in what way?
They are reduced
B cells cannot mature to plasma cells since TH2 cell sare both suppressed and forced to undergo apoptosis
90
Glucocortiocoids affect eosinophil influx in which way?
It is reduced
Eosinophil influx is mediated by IL-5 which comes from TH2 cells - which glucocorticoids suppress
Glucocorticoids can also induce apoptosis of eosinophils
91
By removing IL-4 (suppressing TH2 cells), what other effect is induced by glucocorticoids?
Mast cell recruitment is reduced
92
In which two ways are mast cells affected by glucocorticoids?
1. Their recuitment is reduced (lack of IL-4 due to TH2 supression)
2. Abundance of Fcε receptor on mast cells are downregulated so they are less likely to be activated by IgE
93
How are endothelial cells affected by glucocorticoids?
They become less "leaky" counteracting oedema
94
Give four examples of glucocorticosteroids
1. Beclometasone
2. Budesonide
3. Fluticasone
4. Prednisolone (oral drug)
95
B2 adrenoceptor levels (in airway smooth muscle) are affected by glucocorticoids - in what way?
They are upregulated
They airways become more sensitive to adrenaline and pharmacotherapeutics
96
What are the side effects of glucocorticosteroids?
When taken by inhalation side effects are due to incorrect administration (deposited at the back of throat or swallowed)
* Dysphonia - hoarse and weak voice
* Oropharyngeal candidiasis
The oropharynx becomes immunosuppressed and is vulnerable to infection
97
What is the overarching idea of cromone function?
They are mast cell stabilisers
| (prevent histamine release)
98
How can cromones affect C-fibres?
C-fibres (exposed nerve fibres) have their sensitivity decreased by cromones
99
What is the main cromone administered by inhalation?
Sodium cromoglicate
(targets late phase of asthma and takes several weeks to work)
100
How can monoclonal antibodies be used (against IgE) in the treatment of asthma?
They can be used against IgE
They bind to IgE via the fixed chain preventing any interaction from IgE with the Fcε receptor on mast cells
This prevents mast cell activation
101
Why is monoclonal antibody treatment inconvenient to the patient?
It requires regular IV administration
102
Name a monoclonal antibody treatment against IgE
Omalizumab
103
Name a monoclonal antibody treatment against IL-5 for use in asthma
Mepolizumab
This is for severe asthma with serious eosinophilia
104
Why are monoclonal antibody treatments seldom used despite their effectiveness?
They are very expensive
105
What is the best treatment for COPD?
Smoking cessation
106
COPD is composed of which two branches of disease?
1. Chronic bronchitis
2. Emphysema
107
Describe the pathway to developing COPD
1. A stimulus (smoking) will recruit macrophages resident in alveoli which produce cytokines
2. Neutrophils, CD8+ and macrophages are recruited (this immunological recruitment varies to asthma)
3. Proteases are releases such as elastase along with free radicals which will damage lung tissue as well as original stimulus
4. Resident anti-proteinases cannot inhibit this effect because in smokers they are themselves inhibited
108
Why are glucocorticoids effective in asthma and not COPD?
The immunological components recruited in COPD are different to those of asthma
* COPD - CD8+, neutrophils and macrophages
* Asthma - macrophages, CD4+ and TH2 cells
109
What is chronic bronchitis?
Chronic inflammation of the bronchi and bronchioles
This will include a cough, clear sputum (unless infection is present), increased infection rates and breathlessness
110
What is emphsema?
Distension and damage to alveoli
Destruction of alveoli leading to large dead spaces in the lungs contribting to an increased residual volume
111
The cell bodies for smooth muscle preganglionic neurones are present in the ______ \_\_\_\_\_\_
Brain stem
112
The preganglionic neurones for smooth muscle are part of which nerve?
Vagus
113
Where are smooth muscle postganglionic neurones present?
In the walls of airway smooth muscle
114
Short postganglionic neurones for smooth muscle will release which neurotransmitter onto smooth muscle cells in the airways?
Acetylcholine
115
Stimulation of parasympathetic neurones tht innervate airway smooth muscle has what effect(s)?
1. Bronchoconstriction
2. Increased mucous production
116
What is the difference between nicotinic and muscarinic receptors?
Nitotinic receptors mediate a very fast depolarisation of neurones, whilst muscarinic receptors mediate a much slower depolarisation
117
Where is the M1 receptor located at what is its function?
Postganglionic neurone cell body
It functions to mediate a slow excitatory postsynaptic potential which enhnaces cholinergic reflexes
118
Where is the M2 receptor located and what is its function?
Present at the postganglionic nerve terminals
They function to stimulate the post synaptic receptors on smooth muscle and also muscarinic receptors on the smooth muscle
This is an inhibitory autoreceptor allowing self regulation of acetylcholine release
119
Where is the M3 receptor located and what is its function?
Located on smooth muscle cells (and goblet cells)
They mediate the contraction of smooth muscle in response to acetylcholine stimulation
120
In order to treat COPD which is the main muscarinic receptor that is targeted for inhibition?
M3
(not M2, this helps reduce acetylcholine reduction anyway)
121
Muscarinic acetylcholine receptor antagonists have what outcome?
1. Release of mucous is reduced
2. Smooth muscle contraction is reduced
122
How does the M3 receptor normally confer smooth muscle contraction upon stimulation?
* It is a G-protein coupled receptor which, when activated, will activate Gq11
* The G protein activates phospholipase C which is a membrane bound enzyme
* This converts phosphatidlylinosital (4,5) biphosphaste (PIP2) to the soluble messenger molecule inositol (1, 4, 5) triphosphate (IP3)
* IP3 binds to IP3 receptors on the sarcoplasmic reticulum which induces calcium release allowing for muscle contraction
123
Which two classes of muscarinic receptor antagonists can be utilised to block M3 receptors on smooth muscle and give examples for each
* Short acting muscarinic antagonists (SAMAs) - ipratropium, oxitropium
* Long acting muscarinic antagonists (LAMAs) - tiotropium, aclidinium
124
SAMAs and LAMAs possess a quaternary ammonium group in their structure - why is this signifiant?
Unlike a tertiary group, this is permanent
The postive charge prevents the molecule from travelling systematically and localises it to the airways
This reduces systemic side effects
125
Is ipratropium a selective or non-selective agent?
Non-selective
This means M2 receptors are blocked leading to an increase in acetylcholine production meaning the drug has more work to do on M3 receptor inhibition than it would if it were selective
126
Is tiotropium a selective or non-selective agent?
Selective
It has a longer half-life than ipratropium (34.7 vs 3.2 hours)
127
Muscarinic receptor antagonists are often used in conjunction with what other drug class?
B2 agonists
* SABAs - salbutamol
* LABAs - salmeterol, formeterol
* Ultra LABAs - indacaterol
128
In short, how do B2 agonists function to induce smooth muscle relaxation?
They stimulate B2 adrenoceptors which allows for an increase in cAMP which can activate relaxation mechanisms
129
How do B2 agonists contribute to decreased acetylcholine release?
They are present alongside M2 receptors at the terminals of postganglionic parasympathetic nerve fibres and their stimulation can aid a decrease in acetylcholine release
130
To obatin the best response in COPD treatment, LABAs and LAMAs should be taken \_\_\_\_\_\_\_\_\_
Together
(so that they end up in the same location in the airways)
This is done by creating MABAs
(muscarinic antagonist B2 agonists)
131
Desribe the two ways in which phosphodiesterase inhibitors can aid in COPD treatment
1. They limit the breakdown of cAMP in cells allowing for relaxtion to be mainatined in smooth muscle cells
2. PDE4 is expressed in neutrophils, T cells and macrophages and a build up of cAMP can suppress their function
132
What is the main side effect for using PDE4 inhibitors for COPD?
They have GI side effects
There will be increasted secretions and diarrhoea will result
133
For how long should glucocorticoids be used for COPD?
Only short term
Long term effects are limited and they should just be used to reduce exacerbationsand stabilised the condition
134
Why are glucocorticoids less effective in COPD than in asthma?
1. There are different immunological processes in COPD
2. Oxidative/nitrative stress drives COPD inflammation - something glucocorticoids cannot impact
3. The expression of HDAC2 in COPD sufferers is less so it is harder for glucocorticoids to activate anti-inflammatory genes as the DNA remains more tightly bound
135
What is rhinitis?
A cold-like disease involving:
* Runny nose (rhinorrohea)
* Sneezing
* Itching
* Nasal congestion and obstruction
136
What are the three types of rhinitis?
1. Allergic
2. Non-allergic
3. Mixed (combination of the above types)
137
What is allergic rhinitis?
* A specific allergen, when inhaled, will cause the condition
* A hypersensitivity type 1 reaction will proceed causing IgE levels to rise
* IgE can activate mast cells and basophils
* Pro-inflammatory mediators are released (histamine, CysLTs, trytase and prostaglandins)
* These cause the symptoms
* A delayed component is present due to the recruitment of lymphocytes and eosinophils which causes nasal congestion and obstruction
138
What is non-allergic rhinitis?
It does not have an allergic component do does not involve IgE
Causes can include infection, hormone imbalance, vasomotor disturbances (often idiopathic), non-allergic rhinitis with eosinophila syndrome (NARES) and medications
* Infectious rhinitis is largely viral
* Rhinitis by hormone imbalance often occurs in pregnancy
139
What are the major drug classes for the treatment of rhinitis?
* Glucocorticoids - anti-inflammatory
* CysLT1 receptor antagonists/H1 receptor antagonists - mediator receptor blockers
* Vasoconstrictors - reduce nasal blood flow
* Cromones - sodium chromoglicate - antiallergic
140
Give three examples of glucocorticoids that can be used for rhinitis
1. Prednisolone (orally)
2. Fluticasone
3. Beclometasone
141
What are anti-histamines?
Competitive antagonists of H1 receptors
142
Why are second generation anti-histamines superior to first generations?
They cannot cross the blood brain barrier and do not have anti-cholinergic effects
They also have reduced side effects and are less likely to cause lethargy
Despite this, the anti-cholinergic effects of first generation drugs can combat rhinorrhoea
143
Give 3 examples of second generation anti-histamines
1. Loratadine
2. Fexofenadine
3. Cetirizine (possesses mild inflammatory action)
144
What is the only muscarinic receptor antagonist used for rhinitis?
Ipratropium
145
Which cromone can be used to treat rhinitis and how does it function?
Sodium chromoglicate
Acts as a mast cell stabiliser but has a long onset of action usually between 4-7 days
146
How do CysLT1 receptor antagonists function in the nasal mucosa?
They block the effects of CysLTs
They are equally as effective as H1 receptor antagonists and when used toegther the effect may be additive
147
What is the only CysLT receptor antagonist to treat rhinitis?
Montelukast
148
When will vasoconstriction occur in the nasal mucosa?
When alpha1-adrenoceptors are stimulated
149
What is a selective alpha-1 adrenoceptor used in the treatment of rhinitis?
Oxymetazoline
Treatment for longer than a few days is not recommended since rhinitis medicamentosa may occur - this is when nasal congestion increased to levels worse than before treatment when treatment is eventually stopped
This occurs due to receptor desensitisation and downregulation due to overstimulation
150
Within the lungs, parasympathetic control is ________ over sympathetic control
Dominant
151
How does smoking impact HDAC activity?
It reduces the activity
This means the functioning of corticosteroids in COPD may improve if smoking ceases
152
How does the anti-inflammatory component of tiotropium function?
* Acetylcholine release directly results in LTB4 and IL-8 release from mast cells and bronchial epithelium respectively
* LTB4 increases capillary permeability and adhesiveness
* IL - causes neutrophil activation and chemotaxis
* By blocking LTB4 and IL-8, as tiotropium does, their effects do not occur and inflammation is reduced
153
. An anti-inflammatory that can trigger bronchospasm in sensitive individuals.
Oral ibuprofen
154
A synthetic glucocorticoid used to prevent inflammation in chronic asthma.
Inhaled beclometasone
155
A synthetic glucocorticoid used in severe or rapidly deteriorating asthma.
Oral prednisolone
156
A weak anti-inflammatory drug used which can be useful in children and young adults.
Inhaled sodium cromoglycate
