Pharmacology Of Airway Diseases Flashcards
What occurs in the immediate phase of asthma?
Allergen stimulates mast cells to produce spasmogens of the bronchials & chemotaxins/chemokines
What occurs in the late phase of asthma?
Infiltration of cytokine-released Th2 cells & monocytes
Activation of inflammatory cells particularly eosinophils
Release of mediators & EMBP/ECP (epithelial damage)
Airway inflammation & hyper-reactivity causing bronchospasm, wheezing & coughing
What drug inhibit bronchospasm in asthma?
B2-adrenoceptor agonists
CysLT-receptor antagonists
Theophylline
What drugs can target the inflamamtory response of asthma?
Glucocorticoids
What occurs in COPD gained from smoking?
Tobacco stimulates production of ROS from neutrophils -> IL-, LTB4 & TNF release, inactivation of antiproteases (functional OR congenital α1AT deficiency) + neutrophil elastase increase -> tissue damage -> increased alveolar macrophage elastase & metalloproteinases
= prolonged inflammatory tissue damaging environment
What are the 3 pathophysiological features of airway disease that can be targeted with drugs?
- Neurotransmitter-controlled airway SM contractility
- Airway hyper-responsiveness i.e. acute inflammatory response
- Airway chronic inflammation by targeting IS in lung
What drugs can be used for bronchodilation?
B: B2-agonist
A: Anti-cholinergics
M: Methylxantines
What drugs can be used with anti-inflammatory action?
Lu: Leukotriene receptor antagonists
Glu: Glucocorticoids (AKA corticosteroids)
What are the drugs used for severe acute asthma treatment?
O: O2 S: Salbutamol (B2-agonist) H: Hydrocortisone (glucocorticoid) I: Ipratropium (anticholinergic) T: Theophylline (methylxanthine)
What neurological activity controls lung function?
- SNS mostly via adrenergic nerve fibres releasing noradrenaline drive BRONCHODILATION
- PNS mostly via cholinergic nerve fibres releasing acetylcholine drive BRONCHOCONSTRICTION
How do B2-adrenoceptor agonists (B2-agonists) work?
- Stimulates B2 adrenergic receptor on bronchiolar SMCs
- Increases Adenylate Cyclase (AC) which converts AMP -> cAMP
- cAMP activates PKA
- PKA drives Ca2+ into storage vesicles away from cytoplasm & inactivates MLCK driving dephosphorylation of MLC
- Reduced SMC contraction = bronchodilation
What are some examples of B2-adrenoceptor agonists (B2-agonists)?
Short-acting (3-4hrs): Salbutamol & Terbutaline
Long-acting (12hrs): Salmeterol & Formoterol
What are the key side effects of B2-adrenoceptor agonists (B2 agonists)?
Tremor
Tachycardia
Cardiac arrhythmia
What is the difference between the 2 types of B2-adrenoceptor agonists (B2-agonists)?
Short-acting (relievers): binds to active site of receptor & has affect only once dissociating afterwards
Long-acting (preventers): binds to exosite of receptor allowing molecule to be in constant contact with active site producing its effects over a longer period
How do anticholinergnic drugs work?
- Binds to M3 receptor blocking its active site
- G protein on IC side does not activate PLC as it would when stimulated
- PLC does not produce IP3 & then increase IC Ca2+ levels causing bronchoconstriction
- Instead there is reduced Ca2+ release from IC stores
- This causes reduced SM contraction = bronchodilation
What are some examples of anti-cholinergic drugs?
Short-acting: Ipratropium
Long-acting: Tiotropium
What are the key side effects of anti-cholinergic drugs?
Dry mouth
Constipation
Urinary retention
How do methylxanthines work?
- Phosphodiesterase (PDE) normally inactivates cAMP
- Drugs inhibit PDE sustaining cAMP
- PKA produced
- Reduced phosphorylation of MLC via MLCK & reduced IC Ca2+ = reduced SM contraction
- Bronchodilation
What are some examples of methylxanthines? How are they taken?
Theophylline
Aminiphylline
Either as an oral tablet or IV in acute asthma
What are some key side effects of methylxanthines?
Cardiac arrhythmias
Seizures
Very toxic cardiac & neurological side effects (must monitor serum levels; Ph3)
How does the immune system lead to lung damage and respiratory disease?
- Abnormal & hypersensitive immune response to materials e.g. allergens which activates cells such as MCs & eosinophils
- Mediators released can drive bronchospasm & augment further immune reactions
- Infiltrates of lymphocytes e.g. T cells lead to chronic inflammation -> tissue remodelling & destruction
What are leukotrienes (LT) and how do they work?
Lipid-based signalling molecules with multiple effects in lung via LT receptors (LT-R) which transduce IC signals in response to LT secretion
LT-R on bronchiolar SMC stimulate constriction via PLC activation
LT-R on eosinophils guide eosinophil chemotaxis to sites of inflammation
What are some examples of leukotriene receptor (LT-R) antagonists? How are they taken?
Montelukat
Zafirlukast
As oral tablets
What leukotriene receptor (LT-R) do antagonists act on?
CysLT1
What are the uses of leukotriene receptor (LT-R) antagonists?
Reduce inflammatory responses in early & late phases of asthma
Additive effect when used with other drugs e.g. inhaled glucocorticoids
Used as preventer
What are the side effects of leukotriene receptor (LT-R) antagonists?
Abdominal pain
Headache
Do leukotriene receptor (LT-R) antagonists improve the tissue remodelling seen in chronic asthma?
No evidence of effect
How do glucocorticoids work?
- Stimulate IC glucocorticoid receptor (GR) on immune cells of lungs especially macrophages, T cells & eosinophils
- Activated GR interacts with selected nuclear DNA sequences & influences expression of many key genes
- Suppresses pro-inflammatory mediators e.g. Th2 cytokines (IL-3, IL-5)
- Expresses anti-inflammatory products e.g. lipcortin-1, SLPI & B2-adrenoceptor upregulation
- Reduced inflammation
What are some common examples of glucocorticoids? How are they taken?
Beclomethasone (inhaled)
Fluticasone (inhaled)
Prednisolone (oral)
Hydrocortisone (IV)
What are the key side effects of glucocorticoids?
Many side effects especially with long-term oral glucocorticoids e.g.
Moon face w/ red cheeks
Weight gain (abdominal fat gain)
Osteoporosis
Hyperglycaemia tendency
