L2 - Asthma and COPD Flashcards
1
Q
What are the key characteristics of asthma?
A
Inflammation in the airways
Hyper-reactivity to various stimuli
Reversible airway obstruction
2
Q
What are the common symptoms of asthma?
A
Tight chest
Wheezing (whistling sound)
Dyspnoea (difficulty breathing)
Productive cough (especially during attacks)
Nocturnal coughing (coughing at night)
3
Q
What are the risk factors for asthma?
A
Genetic predisposition (family history of asthma or allergies)
Environmental factors (e.g., air pollution, allergens)
Respiratory infections during early childhood
Exposure to tobacco smoke (either prenatal or second-hand)
Occupational exposure to irritants or allergens (e.g., chemicals, dust)
Obesity
Exposure to allergens (e.g., dust mites, pet dander, pollen)
4
Q
Why is asthma considered a heterogeneous disease?
A
Heterogeneity means that asthma presents differently across individuals.
It can vary in terms of symptoms, triggers, and severity of airway obstruction.
Types of asthma include allergic asthma, non-allergic asthma, exercise-induced asthma, and occupational asthma.
Different patients may respond to treatments in various ways, and there is no single cause for the disease.
Variations in genetic factors, immune responses, and environmental exposures contribute to this diversity.
5
Q
What are the key components of asthma diagnosis?
A
Symptoms
When do symptoms occur?
Identification of triggers (e.g., allergens, exercise, irritants).
Family History
History of allergies or asthma in the family.
Age of Onset
Childhood vs adult onset asthma.
Lung Function Tests
Peak Expiratory Flow Rate (PEFR): Measures the speed of exhalation.
Spirometry (recommended for patients over 5 years old).
Normal FEV1/FVC ratio should be >70%.
Reversibility Test: Measures improvement in lung function after bronchodilator administration.
6
Q
What are the characteristics and triggers of an asthma attack?
A
Characteristics of an Asthma Attack:
Tight chest
Wheezing (whistling sound during exhalation)
Dyspnoea (shortness of breath)
Productive cough (often during attacks)
Nocturnal coughing (coughing at night)
Triggers of Asthma Attacks:
Allergens (e.g., pollen, dust mites, mould, pet dander)
Respiratory infections (e.g., viral or bacterial infections)
Exercise
Cold air
Air pollution
Stress
Medications (e.g., beta-blockers, aspirin)
Chemical irritants (e.g., strong smells, smoke, perfumes)
7
Q
What is hyper-reactivity in asthma, and how does it contribute to the disease?
A
Hyper-reactivity refers to the exaggerated response of the airways to various stimuli, such as allergens, irritants, or exercise.
It leads to bronchoconstriction, where the muscles around the airways tighten, reducing airflow and causing symptoms like wheezing, shortness of breath, and coughing.
Pathophysiology:
In asthma, inflammation and mucus production further narrow the airways.
Exposure to triggers causes immune cell activation (e.g., mast cells, eosinophils), releasing mediators like histamines and leukotrienes, which amplify airway narrowing.
Consequences:
Increased airway resistance, reduced airflow, and difficulty breathing, particularly during an asthma attack.
8
Q
What is sensitisation in the context of asthma, and how does it occur?
A:
A
Sensitisation is the process by which the immune system becomes primed to respond to an allergen, playing a key role in allergic asthma.
Mechanism of Sensitisation:
Allergen exposure: The allergen enters the body and is captured by dendritic cells in the lungs.
The dendritic cells migrate to the lymph nodes where they present the allergen to naive T-helper (Th0) lymphocytes.
These Th0 cells differentiate into Th2 lymphocytes in response to the allergen.
Th2 cells secrete cytokines, primarily IL-4, which promote B-cell activation.
The activated B-cells produce IgE antibodies, specific to the allergen.
IgE binds to the surface of mast cells via FcεRI receptors.
Re-exposure to the allergen:
Upon subsequent exposure to the same allergen, the allergen binds to the IgE on mast cells, leading to mast cell degranulation and release of inflammatory mediators (e.g., histamines, leukotrienes), causing bronchoconstriction and inflammation typical of an asthma attack.
9
Q
What mediators are released during mast cell activation in the immediate phase?
A
Histamine, chymase, tryptase, heparin, leukotrienes (B4, C4,
10
Q
What is the role of histamine during mast cell activation?
A
Histamine increases vascular permeability and causes smooth muscle contraction.
11
Q
What do chymase and tryptase contribute to mast cell activation?
A
Chymase and tryptase promote tissue damage, inflammation, and recruit immune cells.
12
Q
How does heparin function in mast cell activation?
A
Heparin prevents clotting and supports the immune response.
13
Q
What do leukotrienes B4, C4, and D4 do during mast cell activation?
A
Leukotrienes B4 recruit neutrophils, while C4 and D4 cause vasodilation and bronchoconstriction.
14
Q
What is the role of prostaglandin D2 in mast cell activation?
A
Prostaglandin D2 promotes vasodilation and bronchoconstriction.
15
Q
What does TNF do during mast cell activation?
A
TNF promotes inflammation and activates immune cells.
16
Q
What is the role of PAF in mast cell activation?
A
PAF stimulates platelet aggregation and increases vascular permeability.
17
Q
What is the function of interleukins 3, 4, 5, 6, and 13 in mast cell activation?
A
They stimulate immune cell activation, proliferation, and differentiation.
18
Q
What are the effects of inflammatory mediators during the immediate phase?
A
Bronchoconstriction, increased mucous production, vasodilation, increased vascular permeability, and leukocyte recruitment.
19
Q
What mediators contribute to bronchoconstriction?
A
Histamine, PGD2, LTC4.
20
Q
What causes increased mucous production in the immediate phase?
A
PGD2, LTC4.
21
Q
Which mediators contribute to vasodilation in the immediate phase?
A
PGD2, LTC4, TNF.
22
Q
What mediators increase vascular permeability during the immediate phase?
A
Histamine, PGD2, LTC4, TNF, Chymase.
23
Q
Which mediators are involved in leukocyte recruitment during the immediate phase?
A
LTB4, TNF, CCL2.
24
Q
What are the key features of the late-phase response in allergic reactions?
A
Eosinophils, hyper-reactivity, increased airflow resistance, airway remodelling.
25
What are the cytotoxic proteins released by eosinophils during the late-phase response?
Eosinophil cationic protein, major basic protein, eosinophil-derived neurotoxin.
26
Which bronchoconstrictors are involved in the late-phase response?
Cysteinyl leukotrienes.
27
What fibrogenic factor is involved in airway remodelling during the late-phase response?
TGF-β (Transforming Growth Factor Beta).
28
What factors contribute to the progression of asthma?
Increased frequency and severity of asthma attacks, repeated exposure, and inflammation.
29
: How does repeated exposure and inflammation affect asthma?
They lead to airway remodelling, worsening symptoms, and increased asthma severity over time.
30
What are the pharmacological targets for the immediate phase of asthma?
Relievers (bronchodilators) target bronchoconstriction and aim to relieve acute symptoms.
31
What are the pharmacological targets for the late phase of asthma?
Preventers (anti-inflammatory drugs) target inflammation, reducing the risk of chronic airway remodelling and preventing future attacks.
32
What is the pharmacological target of cysteinyl leukotriene antagonists?
Cysteinyl leukotriene antagonists block leukotriene receptors, reducing bronchoconstriction and inflammation.
33
What is the function of β2 agonists in asthma treatment?
β2 agonists relax bronchial smooth muscle, leading to bronchodilation and relief of acute symptoms.
34
How do muscarinic receptor antagonists work in asthma management?
Muscarinic receptor antagonists block acetylcholine binding, preventing bronchoconstriction and reducing airway resistance.
35
What is the role of methylxanthines in asthma treatment?
Methylxanthines inhibit phosphodiesterase, increasing cAMP levels to relax bronchial smooth muscle and enhance bronchodilation.
36
: What is the pharmacological role of glucocorticoids (Glu) in asthma?
Glucocorticoids reduce inflammation, inhibit immune responses, and prevent airway remodelling in chronic asthma.
37
What is the effect of short-acting β2-adrenoceptor agonists (SABA)?
SABAs provide rapid bronchodilation, offering quick relief from acute asthma symptoms by relaxing bronchial smooth muscle.
38
How do long-acting β2-adrenoceptor agonists (LABA) differ from SABAs?
LABAs provide prolonged bronchodilation, used for maintenance treatment to control asthma symptoms over a longer period.
39
What is the role of ultra-long acting β2-adrenoceptor agonists (ultra-LABA)?
Ultra-LABAs provide very prolonged bronchodilation, typically used for once-daily maintenance therapy in chronic asthma or COPD management.
40
What are the common adverse effects of β2-adrenoceptor agonists related to β1 and β2 stimulation?
Tachycardia, arrhythmias, myopathy, and ischaemia, especially when used with theophylline.
41
What β2-specific adverse effects can occur with β2-adrenoceptor agonists?
Tachycardia due to vasodilation and decreased venous return.
Q3
42
What other adverse effects are associated with β2-adrenoceptor agonists?
Hypertrophy, hyperglycaemia, and hypokalaemia.
43
What is the function of M1 muscarinic receptors?
M1 receptors increase parasympathetic transmission, promote water and electrolyte secretion, and enhance ciliary beat (when M1/2 are blocked).
44
Where are M1 receptors expressed?
M1 receptors are expressed in the epithelium and ganglia.
45
What is the function of M2 muscarinic receptors?
M2 receptors cause smooth muscle contraction, limit acetylcholine release, and decrease ciliary beat.
46
Where are M2 receptors expressed?
M2 receptors are found in smooth muscle, parasympathetic neurons, and the epithelium.
47
hat is the function of M3 muscarinic receptors?
M3 receptors cause smooth muscle contraction, mucous secretion, vasodilation, and increase ciliary beat.
48
Where are M3 receptors expressed?
M3 receptors are expressed in smooth muscle, submucosal glands, endothelium, and epithelium.
49
How does acetylcholine (ACh) affect muscarinic receptors in the airway?
ACh binds to M3 receptors, causing smooth muscle contraction, and to M2 receptors, which limit acetylcholine release. M1 receptors also enhance parasympathetic transmission.
50
What role does the vagus nerve play in muscarinic receptor activation?
The vagus nerve releases acetylcholine, stimulating muscarinic receptors on airway smooth muscle, leading to contraction.
51
Why are muscarinic antagonists limited in their use?
Muscarinic antagonists are limited due to their lack of subtype selectivity, meaning they can affect multiple muscarinic receptor types (M1, M2, M3) with varying effects.
52
What is the mechanism of action of atropine as a muscarinic antagonist?
Atropine blocks muscarinic receptors, preventing acetylcholine from binding, thus inhibiting parasympathetic effects such as smooth muscle contraction and secretions.
53
What are the primary effects of atropine on the respiratory system?
Atropine causes bronchodilation, reduces mucus secretion, and inhibits vagal-induced bronchoconstriction.
54
What are some common uses of atropine in clinical practice?
Atropine is used to treat bradycardia, reduce secretions during surgery, and manage organophosphate poisoning.
55
What are the major side effects of atropine?
Dry mouth, blurred vision, urinary retention, constipation, and tachycardia due to reduced parasympathetic activity.
56
What is the difference between short-acting muscarinic antagonists (SAMA) and long-acting muscarinic antagonists (LAMA)?
SAMAs provide quick relief by blocking muscarinic receptors for a short duration, while LAMAs offer prolonged bronchodilation and are used for maintenance therapy.
57
What are common examples of short-acting muscarinic antagonists (SAMA)?
Ipratropium bromide is a common SAMA used for acute asthma or COPD exacerbations.
58
What are common examples of long-acting muscarinic antagonists (LAMA)?
Tiotropium and aclidinium are examples of LAMAs, used for long-term management of asthma and COPD.
59
What is the primary effect of both SAMAs and LAMAs in the respiratory system?
Both SAMAs and LAMAs block muscarinic receptors, causing bronchodilation and reducing mucus secretion in the airways.
60
What are the adverse effects of muscarinic antagonists related to M2 receptors?
Tachycardia due to reduced parasympathetic influence on the heart.
61
What adverse effects are associated with M3 receptor antagonism?
Dry mouth, dry skin, sore throat, and dilation of pupils (leading to photophobia).
62
How do muscarinic antagonists affect the central nervous system (CNS)?
Antagonism of M1, M4, and M5 receptors can cause headache, dizziness, and confusion.
63
What gastrointestinal and urinary effects are caused by muscarinic antagonists?
Constipation and urinary retention due to reduced parasympathetic activity on smooth muscle.
64
What is the mechanism of action of methylxanthines like caffeine and theophylline?
Methylxanthines inhibit phosphodiesterase, increasing cAMP levels, leading to bronchodilation and anti-inflammatory effects.
65
What are the effects of caffeine on the body?
Caffeine acts as a mild bronchodilator, increases alertness, and stimulates the central nervous system by inhibiting adenosine receptors.
66
What is the role of theophylline in respiratory conditions?
Theophylline is used to treat asthma and COPD by relaxing bronchial smooth muscle and improving airflow, while also having anti-inflammatory properties.
67
What are the common side effects of methylxanthines (caffeine and theophylline)?
Tachycardia, insomnia, nausea, headache, and in higher doses, arrhythmias and seizures.
68
What is the mechanism of action of theophylline as described by Barnes (2013)?
Theophylline works primarily by inhibiting phosphodiesterase (PDE), increasing cyclic AMP (cAMP) levels, leading to bronchodilation. It also antagonises adenosine receptors, which helps reduce bronchoconstriction and has anti-inflammatory effects. Additionally, it enhances diaphragmatic contractility and improves mucociliary clearance.
69
What other effects does theophylline have, according to Barnes (2013)?
Theophylline also has immunomodulatory effects, reducing the release of pro-inflammatory cytokines, decreasing eosinophil activation, and promoting the resolution of inflammation in the airways.
70
How does theophylline affect airway smooth muscle and epithelium?
Theophylline reduces the effects of proinflammatory mediators, inhibits mucous secretion, and decreases bronchoconstriction. It promotes smooth muscle relaxation and reduces airway inflammation by modulating both Gs (stimulatory) and Gi (inhibitory) pathways.
71
How does theophylline influence proinflammatory mediators?
Theophylline inhibits the release of proinflammatory mediators and reduces the activation of inflammatory cells, contributing to its anti-inflammatory effects in the airways.
72
What is the role of A1 adenosine receptors (A1AR) in the airway as described by Barnes (2013)?
A1AR activation, via Gi (inhibitory) pathways, promotes bronchoconstriction and enhances the release of proinflammatory mediators from immune cells, contributing to airway inflammation and narrowing.
73
What is the role of A2A adenosine receptors (A2AAR) in the airway?
A2AAR activation, through Gs (stimulatory) pathways, reduces proinflammatory mediator release, decreases mucous secretion, and prevents bronchoconstriction, exerting anti-inflammatory effects.
74
How does theophylline affect adenosine receptors?
Theophylline antagonises A1AR and A2AAR, leading to a reduction in bronchoconstriction, decreased proinflammatory mediator release, and inhibition of mucous secretion. This enhances bronchodilation and anti-inflammatory effects.
75
How does theophylline impact mast cells?
Theophylline inhibits mast cell degranulation, reducing the release of histamine and other inflammatory mediators, thus contributing to its anti-inflammatory effects in asthma and COPD management.
76
How does theophylline affect gene transcription in immune cells as described by Barnes (2013)?
Theophylline influences gene transcription by inhibiting the activation of inflammatory genes and promoting the activation of anti-inflammatory genes. It inhibits co-activators like HAT (histone acetyltransferase) and activates HDAC (histone deacetylase), which represses inflammatory gene transcription.
77
What is the role of nuclear factors like p65 and p50 in theophylline's mechanism of action?
p65 and p50 are components of the NF-κB pathway that regulate inflammatory gene transcription. Theophylline inhibits the activity of p65 and p50, reducing inflammatory gene activation and enhancing anti-inflammatory effects.
78
How does theophylline interact with corticosteroids in gene regulation?
Theophylline enhances corticosteroid activity by increasing the activity of the glucocorticoid receptor (GR), which further inhibits inflammatory gene transcription and promotes anti-inflammatory gene expression.
79
What effect does theophylline have on inflammatory stimuli?
Theophylline reduces the effects of inflammatory stimuli by inhibiting the transcription of inflammatory genes and promoting the expression of anti-inflammatory genes through its interaction with various nuclear factors and co-activators.
80
What are the key pharmacokinetic properties of theophylline?
Theophylline has a high oral bioavailability, a narrow therapeutic window, and is metabolised by the liver, primarily through cytochrome P450 enzymes (especially CYP1A2). Its half-life can be influenced by age, liver function, and smoking status.
81
How is theophylline distributed in the body?
Theophylline is widely distributed, including in the lungs, and is about 40-60% protein-bound in the plasma.
82
How is theophylline eliminated from the body?
Theophylline is primarily eliminated via renal excretion, with some metabolism occurring in the liver. Its clearance is affected by factors like liver disease, age, and concomitant drug use (e.g., smoking decreases its clearance).
Q4
83
What factors affect theophylline's metabolism and half-life?
Factors that affect theophylline’s metabolism include liver function, age, smoking, and drug interactions (e.g., enzyme inhibitors like ciprofloxacin increase theophylline levels, while enzyme inducers like rifampicin decrease them). Its half-life is typically around 8 hours but can vary.
84
What is the therapeutic range for theophylline plasma concentration?
he therapeutic range for theophylline plasma concentration is typically between 10-20 mg/L.
85
What are some common side effects of theophylline when plasma levels are within the therapeutic range?
Common side effects include nausea and vomiting, abdominal discomfort, gastroesophageal reflux, diuresis, headache, fainting, and tachycardia.
86
What are the toxic effects of theophylline when plasma levels exceed the therapeutic range?
Toxic effects include cardiac arrhythmias, convulsions, and status asthmaticus. In severe cases, particularly with intravenous administration, theophylline toxicity can lead to death.
87
What should be done in the case of theophylline toxicity?
In cases of toxicity, especially in emergencies like status asthmaticus or seizures, IV treatment and close monitoring are required to manage the overdose, which may include the use of activated charcoal or other interventions.
88
What are the key cysteinyl leukotriene receptors and their ligands?
The key cysteinyl leukotriene receptors are CysLT1 and CysLT2. They are activated by cysteinyl leukotrienes: LTC4, LTD4, LTE4, and LTF4.
89
What is the role of CysLT1 receptors in the airway?
CysLT1 receptors, which are expressed on leukocytes and airway smooth muscle, mediate bronchoconstriction, leukocyte activation, and inflammation. LTD4 is the most potent ligand for CysLT1, followed by LTC4 and LTE4.
90
What is the function of CysLT2 receptors?
CysLT2 receptors are expressed on leukocytes and vascular smooth muscle. They mediate leukocyte activation and vasoconstriction. LTC4 is the most potent ligand for CysLT2, followed by LTD4 and LTE4.
91
How do CysLT1 and CysLT2 receptors activate intracellular signalling?
Both CysLT1 and CysLT2 receptors are Gq/11-coupled, leading to the activation of phospholipase C (PLC) and subsequent downstream effects like increased intracellular calcium and inflammation.
92
What is the mechanism of action of montelukast and zafirlukast?
Montelukast and zafirlukast are leukotriene receptor antagonists that selectively block the CysLT1 receptor, inhibiting the effects of cysteinyl leukotrienes (LTC4, LTD4, LTE4) such as bronchoconstriction and inflammation in asthma and allergic rhinitis.
93
What is the main difference between montelukast and zafirlukast?
Montelukast is a once-daily oral medication with fewer drug interactions, while zafirlukast is typically taken twice daily and has more drug interactions due to its metabolism by cytochrome P450 enzymes.
94
What are the therapeutic uses of montelukast and zafirlukast?
Both montelukast and zafirlukast are used for the prevention and long-term management of asthma and allergic rhinitis. They help reduce symptoms and prevent asthma exacerbations.
95
What are common side effects of montelukast and zafirlukast?
Common side effects include headache, gastrointestinal disturbances (e.g., nausea, diarrhoea), and in rare cases, mood changes or psychiatric symptoms. Zafirlukast may also cause liver enzyme elevation.
96
What is the mechanism of action of inhaled glucocorticoids as described by Barnes (2013)?
Inhaled glucocorticoids act by binding to the glucocorticoid receptor (GR), which then translocates to the nucleus and binds to glucocorticoid response elements (GRE) in the DNA. This promotes the transcription of anti-inflammatory genes (trans-activation) and represses the transcription of proinflammatory genes (cis-repression).
97
What are the key components involved in glucocorticoid-induced trans-activation and cis-repression?
In trans-activation, the glucocorticoid receptor (GR) recruits co-activators like CBP (CREB-binding protein) and HAT (histone acetyltransferase), leading to increased anti-inflammatory gene transcription. In cis-repression, GR interacts with negative glucocorticoid response elements (GRE), inhibiting the transcription of proinflammatory genes.
98
What are the main effects of inhaled glucocorticoids on inflammation?
Inhaled glucocorticoids reduce inflammation by inhibiting the transcription of proinflammatory cytokines and other mediators, leading to decreased airway inflammation, reduced mucus production, and prevention of asthma exacerbations.
99
What are the common adverse effects of inhaled glucocorticoids?
Common adverse effects include oral candidiasis (thrush), hoarseness, and sore throat. Long-term use may lead to systemic effects such as adrenal suppression, bone density loss, and growth inhibition in children.
100
How do inhaled glucocorticoids exert their anti-inflammatory effects at the molecular level as described by Barnes (2013)?
Inhaled glucocorticoids bind to the glucocorticoid receptor (GR), leading to its activation. The activated GR then translocates to the nucleus and binds to glucocorticoid response elements (GRE), which activates the transcription of anti-inflammatory genes (gene activation). This involves the recruitment of co-activators like CBP, HAT, SRC-2, and pCAF, which enhance the transcription process.
101
What is the role of CBP, HAT, SRC-2, and pCAF in glucocorticoid action?
CBP (CREB-binding protein), HAT (histone acetyltransferase), SRC-2 (steroid receptor coactivator-2), and pCAF (p300/CBP-associated factor) are co-activators that interact with the glucocorticoid receptor (GR) to facilitate the transcription of anti-inflammatory genes by promoting chromatin remodelling and enhancing gene expression.
Q3
102
How do inhaled glucocorticoids cause gene repression in inflammation?
In addition to gene activation, glucocorticoids can also cause gene repression by interacting with negative glucocorticoid response elements (GRE) in the promoter regions of pro-inflammatory genes. This prevents the transcription of genes involved in inflammation, further reducing the inflammatory response.
103
What are the overall effects of inhaled glucocorticoids on inflammation and immune response?
Inhaled glucocorticoids reduce inflammation by upregulating anti-inflammatory genes and repressing pro-inflammatory genes. This leads to a decrease in airway inflammation, reduced mucus secretion, and prevention of asthma exacerbations, making them effective in long-term asthma management.
104
How do corticosteroids regulate gene transcription in the immune response?
Corticosteroids bind to the glucocorticoid receptor (GR), which translocates to the nucleus and binds to glucocorticoid response elements (GRE) in the DNA. This interaction activates anti-inflammatory gene transcription (gene activation) and represses pro-inflammatory gene transcription (gene repression
105
What is the role of co-activators like CBP, HAT, and HDAC in corticosteroid action?
Co-activators like CBP (CREB-binding protein) and HAT (histone acetyltransferase) facilitate gene activation by enhancing the transcription of anti-inflammatory genes. HDAC (histone deacetylase), on the other hand, is involved in gene repression by inhibiting the transcription of pro-inflammatory genes, promoting anti-inflammatory effects.
106
What is the involvement of nuclear factors like p65 and p50 in corticosteroid action?
p65 and p50 are components of the NF-κB pathway, which is involved in the transcription of pro-inflammatory genes. Corticosteroids inhibit the activation of p65 and p50, thereby suppressing the inflammatory response by preventing the transcription of pro-inflammatory cytokines.
107
How do corticosteroids balance gene activation and repression in inflammation?
Corticosteroids balance gene activation and repression by enhancing the transcription of anti-inflammatory genes through co-activators (e.g., CBP, HAT) and inhibiting the transcription of pro-inflammatory genes by interacting with negative elements like HDAC and suppressing the activity of nuclear factors like p65 and p50.
108
What are the desired effects of inhaled glucocorticoids on the lungs and immune system?
Inhaled glucocorticoids exert their desired effects by reducing inflammation in the lungs. They work by inhibiting the activation and differentiation of Th2 lymphocytes and the production of IgE by B-cells. This reduces the recruitment of inflammatory cells like mast cells and dendritic cells, preventing the allergic response and asthma exacerbations upon re-exposure to allergens.
109
How do inhaled glucocorticoids impact the immune response in lymph nodes?
In the lymph nodes, inhaled glucocorticoids reduce the differentiation of Th0 lymphocytes into Th2 lymphocytes, which are responsible for promoting the allergic response. By inhibiting the production of IL-4 and IgE, corticosteroids prevent IgE-mediated mast cell activation and the subsequent inflammatory cascade upon allergen re-exposure.
110
What is the role of mast cells in the immune response, and how do corticosteroids affect them?
Mast cells play a central role in allergic reactions by releasing histamine and other inflammatory mediators when activated by IgE receptors (FcεRI). Corticosteroids prevent mast cell activation by reducing IgE production and inhibiting the overall allergic immune response, thereby reducing symptoms like bronchoconstriction and inflammation.
111
How do inhaled glucocorticoids prevent re-exposure to allergens from triggering an inflammatory response?
Inhaled glucocorticoids reduce the migration and activation of inflammatory cells, including dendritic cells and Th2 lymphocytes. They also inhibit the differentiation of these cells and the release of IL-4, which is essential for IgE production and mast cell activation. This reduces the likelihood of an inflammatory response upon re-exposure to allergens.
112
How do corticosteroids, including inhaled glucocorticoids, produce their desired anti-inflammatory effects?
Inhaled glucocorticoids, through binding to the glucocorticoid receptor (GR), induce the expression of Annexin-1, which then inhibits phospholipase A2 (PLA2). This reduces the production of pro-inflammatory mediators, such as arachidonic acid, and subsequently decreases the synthesis of inflammatory eicosanoids like prostaglandins and leukotrienes, leading to reduced inflammation.
113
What is the role of Annexin-1 in corticosteroid action?
Annexin-1 is a protein induced by corticosteroids that has anti-inflammatory effects. It inhibits PLA2 activity, reducing the release of arachidonic acid, a precursor for pro-inflammatory mediators, thus contributing to the suppression of inflammation in the airways.
114
How do inhaled glucocorticoids help prevent inflammation in asthma and allergic conditions?
Inhaled glucocorticoids reduce airway inflammation by decreasing the production of pro-inflammatory cytokines and mediators. They enhance Annexin-1 expression, inhibit PLA2 activity, and reduce the synthesis of inflammatory eicosanoids, which collectively diminish inflammation, mucus production, and airway hyperresponsiveness.
115
What are the specific effects of corticosteroids on PLA2 and inflammatory pathways?
Corticosteroids suppress the activation of PLA2, an enzyme responsible for the release of arachidonic acid from phospholipids. This reduction in arachidonic acid limits the production of inflammatory mediators, such as prostaglandins and leukotrienes, thus controlling inflammation and preventing exacerbations in conditions like asthma.
116
How do inhaled corticosteroids synergise with β2-adrenoceptor agonists (LABAs) in asthma treatment?
Inhaled corticosteroids enhance the anti-inflammatory effects of β2-adrenoceptor agonists (LABAs) by increasing the translocation of the glucocorticoid receptor (GR) to the nucleus. This leads to increased binding to glucocorticoid response elements (GRE) and upregulation of anti-inflammatory gene expression. The combination improves bronchodilation and helps prevent the tolerance commonly associated with LABA use.
117
What is the effect of corticosteroids on β2-adrenoceptor expression and coupling?
Corticosteroids increase β2-adrenoceptor expression and improve receptor coupling, making the airway smooth muscle more responsive to β2-adrenoceptor agonists (LABAs). This enhances the bronchodilator effect and helps sustain their efficacy over time, preventing tolerance.
118
How does the synergy between corticosteroids and β2-adrenoceptor agonists improve asthma management?
The combination of corticosteroids and LABAs provides a dual effect: corticosteroids address the underlying inflammation by increasing GR activity and anti-inflammatory gene expression, while LABAs provide bronchodilation. This combined action improves symptom control and allows LABAs to be used as a reliever medication without leading to tolerance.
119
Why is the combination of corticosteroids and LABAs beneficial in asthma treatment?
The synergy between corticosteroids and LABAs is beneficial because corticosteroids enhance the anti-inflammatory action of LABAs and prevent the development of tolerance, while LABAs provide rapid bronchodilation. Together, they improve overall asthma control by managing both inflammation and airway constriction.
120
What is the typical absorption rate of inhaled glucocorticoids, and how does it depend on technique?
Inhaled glucocorticoids are typically absorbed at a rate of ~10-20%. This absorption is dependent on inhalation technique, and using a spacer can improve the delivery of the medication to the lungs, increasing its efficacy.
121
What happens to the portion of inhaled glucocorticoids that is swallowed?
Around ~80-90% of inhaled glucocorticoids are swallowed and absorbed through the gastrointestinal (GI) tract. This portion is subject to first-pass metabolism in the liver, where the drug is inactivated before entering systemic circulation.
122
How does the use of a spacer affect the pharmacokinetics of inhaled glucocorticoids?
The use of a spacer improves the technique of inhalation, resulting in better deposition of the glucocorticoid in the lungs, thus increasing its effectiveness. It also reduces the amount of the drug that is swallowed and absorbed via the gastrointestinal tract, potentially lowering the risk of systemic side effects.
Q4
123
How do glucocorticoids undergo metabolism after absorption, and what is the significance of first-pass metabolism?
Once absorbed through the GI tract, swallowed glucocorticoids undergo first-pass metabolism in the liver, where they are inactivated before entering systemic circulation. This reduces the amount of active drug that reaches the bloodstream, limiting the potential for systemic side effects.
124
What are some systemic side effects of glucocorticoids?
Common systemic side effects of glucocorticoids include oral thrush and stunted growth, especially with prolonged use or high doses.
125
How does oral thrush occur as a side effect of glucocorticoids?
Oral thrush occurs when glucocorticoids are inhaled and cause an imbalance in oral flora, allowing for fungal overgrowth, such as Candida. This is more common when corticosteroids are used without proper rinsing of the mouth after use.
126
How can glucocorticoid use lead to stunted growth?
Prolonged use of glucocorticoids, especially in children, can interfere with growth by inhibiting growth hormone secretion and suppressing bone development. This can result in reduced growth velocity during childhood.
127
How do exogenous glucocorticoids affect the hypothalamus-pituitary-adrenal (HPA) axis?
Exogenous glucocorticoids can suppress the HPA axis by inhibiting the release of corticotropin-releasing factor (CRF) from the hypothalamus and adrenocorticotropic hormone (ACTH) from the anterior pituitary. This leads to reduced stimulation of the adrenal cortex and decreased endogenous cortisol production.
Q2
128
What is the impact of prolonged use of exogenous glucocorticoids on the adrenal cortex?
Prolonged use of exogenous glucocorticoids suppresses the adrenal cortex's ability to produce cortisol. This can lead to adrenal insufficiency, where the adrenal glands fail to produce adequate cortisol during times of stress or when glucocorticoids are withdrawn.
129
Why is the suppression of the HPA axis a concern with long-term glucocorticoid use?
The suppression of the HPA axis is concerning because it can impair the body's ability to produce cortisol naturally. In cases of acute stress or during glucocorticoid withdrawal, this can lead to symptoms of adrenal insufficiency, including fatigue, weakness, and hypotension.
130
What are the two main types of inhalers based on propellant usage?
The two main types of inhalers are those that use a propellant gas, specifically hydrofluoroalkane (HFA), and those that do not use a propellant gas.
131
How do inhalers using hydrofluoroalkane (HFA) work?
Inhalers that use hydrofluoroalkane (HFA) as a propellant release the medication as an aerosol when the inhaler is actuated. The HFA helps to carry the medication into the lungs, allowing for more effective delivery.
132
What is the difference between inhalers that use propellant gas and those that do not?
Inhalers with propellant gas, such as those containing HFA, use the propellant to help deliver the medication to the lungs. In contrast, inhalers without propellant gas rely on the patient’s own inhalation effort to draw the medication into the lungs, such as dry powder inhalers (DPIs).
133
What are the key characteristics of Chronic Obstructive Pulmonary Disease (COPD)?
COPD is a common and preventable disease characterised by persistent respiratory symptoms, including a chesty cough, wheezing, increasing breathlessness, and frequent chest infections.
134
What clinical features are commonly associated with COPD?
The clinical features of COPD include a persistent chesty cough, persistent wheeze, increasing breathlessness (especially during physical activity), and frequent chest infections
135
Why is COPD considered a preventable disease?
COPD is considered preventable because its primary cause, cigarette smoking, can be avoided. Early diagnosis and lifestyle changes, such as smoking cessation, can prevent or slow disease progression.
136
How do the symptoms of COPD differ from those of asthma?
In COPD, symptoms include increasing breathlessness, a persistent chesty cough, frequent chest infections, and persistent wheeze, which progressively worsen over time. In asthma, symptoms are episodic, including breathlessness and wheeze during episodes, with cough associated with these episodes. Chest infections are less common in asthma.
137
How do the underlying causes and progression of COPD and asthma differ?
COPD is not hereditary and typically presents in the elderly, with symptoms progressively worsening. Asthma, however, may have some hereditary links and can present at any age. Asthma is characterised by airway hyper-sensitivity and periods where symptoms can worsen (such as during an attack), while COPD symptoms tend to get worse over time without episodic flare-ups.
138
What are the differences in the frequency and severity of symptoms in COPD versus asthma?
In COPD, symptoms progressively worsen and are persistent, while in asthma, the frequency and severity of symptoms can worsen if untreated, but the symptoms are episodic, often linked to triggers. COPD tends to have chronic and consistent symptoms, while asthma has intermittent flare-ups.
139
What are the key inflammatory cells involved in the pathology of COPD?
The key inflammatory cell in COPD pathology is the neutrophil. Other involved cells include macrophages, monocytes, Tc1 cells, Th1 cells, and fibroblasts.
Q2
140
How does the inflammatory response contribute to COPD pathology?
The inflammatory response in COPD leads to the release of chemokines (CXCL9, 10, 11) and growth factors like TGFβ, which promote neutrophil activation, elastase release, and matrix metalloproteinase (MMP) activity. This results in mucous secretion, emphysema, and fibrosis.
141
What structural changes occur in the lungs as a result of COPD?
In COPD, there is no bronchial wall hypertrophy, but there is high parasympathetic tone, epithelial shedding, loss of cilia, oedema, and damage to the alveolar extracellular matrix, leading to loss of elasticity and increased air space (emphysema). This causes a decline in lung function.
142
How does the loss of alveolar extracellular matrix contribute to emphysema in COPD?
The loss of the alveolar extracellular matrix reduces the elasticity of the lungs, leading to the enlargement of air spaces (emphysema), which impairs the ability to efficiently exchange gases in the lungs.
143
What is the first-line pharmacological intervention for COPD symptoms?
For COPD symptoms, offer a short-acting beta-agonist (SABA) or short-acting muscarinic antagonist (SAMA) as needed for relief of symptoms.
144
When should inhaled corticosteroids (ICS) be considered for COPD treatment?
Inhaled corticosteroids (ICS) should be considered for patients with asthma features suggesting steroid responsiveness, such as day-to-day symptoms or 1 severe or 2 moderate exacerbations in 1 year. A 3-month trial of LABA, LAMA, and ICS can be considered.
145
What treatment is recommended for patients with moderate to severe COPD symptoms?
For patients with moderate to severe symptoms, a combination of LABA (long-acting beta-agonist), LAMA (long-acting muscarinic antagonist), and ICS (inhaled corticosteroid) is recommended. This combination helps manage symptoms and reduce exacerbations.
146
How should treatment be adjusted for patients with frequent exacerbations?
For patients with frequent exacerbations (1 severe or 2 moderate exacerbations in 1 year), a combination of LABA, LAMA, and ICS should be considered. If symptoms persist or worsen, further treatment adjustments should be explored.
147
What are some common adverse effects of Roflumilast?
Common adverse effects of Roflumilast include diarrhoea, weight loss, appetite loss, nausea, back pain, insomnia, and respiratory infections such as influenza.
148
How can Roflumilast impact weight and appetite?
Roflumilast can cause weight loss and a decrease in appetite, which may lead to unintended weight reduction.
Q3
149
What are the respiratory-related adverse effects of Roflumilast?
Respiratory-related adverse effects of Roflumilast include an increased risk of respiratory infections, such as influenza.
150
What are the key non-pharmacological interventions for COPD management?
Key non-pharmacological interventions for COPD management include smoking cessation, pulmonary rehabilitation, long-term oxygen therapy (for FEV <30% of normal), bullectomy, and lung transplantation.
151
When is long-term oxygen therapy recommended in COPD?
Long-term oxygen therapy is recommended for patients with an FEV (forced expiratory volume) of less than 30% of normal, particularly when there is evidence of chronic hypoxaemia.
152
What is the role of pulmonary rehabilitation in COPD management?
Pulmonary rehabilitation is a programme of exercise, education, and support designed to help patients with COPD improve their lung function, exercise tolerance, and quality of life, and reduce hospital admissions.
153
In what cases may surgical interventions like bullectomy or lung transplantation be considered in COPD?
Surgical interventions such as bullectomy (removal of large air spaces or bullae) or lung transplantation may be considered for severe cases of COPD that do not respond to medical treatment and significantly impair lung function and quality of life.
154
How do asthma and COPD differ in terms of inflammation and triggers?
Asthma is characterised by variable inflammation with triggers such as allergens, whereas COPD is a progressive disease with persistent inflammation that is primarily driven by environmental factors like smoking.
155
How do pharmacological treatments overlap in asthma and COPD?
There is significant pharmacological overlap between asthma and COPD, with treatments like bronchodilators, inhaled corticosteroids, and other anti-inflammatory agents being used in both conditions.
156
Why are inhaled corticosteroids more effective in asthma than in COPD?
Inhaled corticosteroids are more effective in asthma due to the reversible nature of the inflammation in asthma, which responds well to steroid treatment. In COPD, the inflammation is more persistent and often less responsive to corticosteroids.
157
What is the role of tissue remodelling in asthma and COPD?
Both asthma and COPD involve tissue remodelling, but in asthma, it is typically reversible, while in COPD, the remodelling is irreversible, contributing to the progressive loss of lung function.
158
How does the progression of COPD differ from asthma?
COPD is a progressive disease that worsens over time, often leading to more severe symptoms and reduced lung function, whereas asthma symptoms may worsen during exacerbations but can often be managed and controlled with treatment.
159
How do the pathophysiologies of asthma and COPD differ?
A1:
Asthma is characterised by reversible airway obstruction and inflammation primarily due to immune responses (often triggered by allergens). This leads to bronchoconstriction, increased mucous production, and airway remodelling over time.
COPD involves chronic inflammation that is irreversible, often due to long-term exposure to noxious particles, such as cigarette smoke. It results in persistent airway obstruction, emphysema (alveolar damage), and fibrosis, leading to lung function decline over time.
Q2
160
What are the mechanisms of action of different classes of drugs used to treat asthma and COPD?
Bronchodilators:
β2-adrenoceptor agonists (SABA/LABA) stimulate β2 receptors, causing smooth muscle relaxation and bronchodilation.
Muscarinic antagonists (SAMA/LAMA) block acetylcholine from binding to muscarinic receptors, preventing smooth muscle contraction.
Methylxanthines (e.g., theophylline) inhibit phosphodiesterase, increasing cAMP levels, leading to bronchodilation.
Anti-inflammatory drugs:
Inhaled corticosteroids (ICS) reduce inflammation by modulating gene transcription and decreasing pro-inflammatory mediator production.
Leukotriene receptor antagonists (LTRA) block leukotriene receptors (CysLT1/2), preventing bronchoconstriction and inflammation.
Phosphodiesterase-4 inhibitors (e.g., roflumilast) reduce inflammation by inhibiting the breakdown of cAMP, leading to reduced pro-inflammatory cytokine release.
COPD-specific:
Long-acting bronchodilators (LABA/LAMA) are used to treat the persistent symptoms and airflow limitation characteristic of COPD.
161
What is the pharmacokinetic profile of drugs used to treat asthma and COPD?
Inhaled corticosteroids (ICS):
Absorption: Low systemic absorption due to local delivery via inhalers.
Metabolism: Hepatic via CYP450 enzymes.
Excretion: Primarily in the urine.
β2-adrenoceptor agonists (SABA/LABA):
Absorption: Rapidly absorbed when inhaled.
Metabolism: Hepatic, with some drugs being partially metabolised by COMT (catechol-O-methyltransferase).
Excretion: Renal, as inactive metabolites.
Muscarinic antagonists (SAMA/LAMA):
Absorption: Systemically absorbed after inhalation but primarily acts locally.
Metabolism: Hepatic metabolism.
Excretion: Renal excretion.
Leukotriene receptor antagonists (LTRA):
Absorption: Oral absorption with high bioavailability.
Metabolism: Hepatic metabolism via CYP enzymes.
Excretion: Primarily renal.
162
What are the adverse effects of drugs used to treat asthma and COPD, particularly anti-inflammatories?
Inhaled corticosteroids (ICS):
Common side effects: Oral thrush, hoarseness, and sore throat.
Systemic side effects (rare with inhalation): Cushing's syndrome, osteoporosis, and growth suppression in children.
Leukotriene receptor antagonists (LTRA):
Common side effects: Headache, gastrointestinal disturbances (nausea, diarrhoea), and rare liver dysfunction.
Neuropsychiatric effects: Anxiety, depression, and sleep disturbances in some patients.
β2-adrenoceptor agonists (SABA/LABA):
Common side effects: Tachycardia, tremors, headache, and muscle cramps.
LABA-specific: Risk of tolerance with long-term use.
Muscarinic antagonists (SAMA/LAMA):
Common side effects: Dry mouth, blurred vision, urinary retention, and constipation.
Methylxanthines (e.g., theophylline):
Toxicity: Nausea, vomiting, arrhythmias, seizures, and even death in high concentrations.
163
How does treatment differ between asthma and COPD, and why are some drugs more or less effective?
Asthma:
Inhaled corticosteroids (ICS) are the cornerstone of treatment, as asthma involves reversible inflammation that responds well to steroids. LABA and LAMA are often added in cases of severe asthma to provide additional bronchodilation.
Leukotriene receptor antagonists (LTRA) are effective due to the role of leukotrienes in inflammation and bronchoconstriction in asthma.
COPD:
Inhaled corticosteroids are less effective in COPD because the inflammation is more resistant to steroids, and the disease is irreversible. Bronchodilators like LABA and LAMA are more central to treatment, as they target persistent airflow limitation.
Phosphodiesterase-4 inhibitors (e.g., roflumilast) are more commonly used in COPD to reduce inflammation and prevent exacerbations, as they help modulate the immune response that drives disease progression.
