Pharmacology of Inflammation and Immunosuppression Flashcards
How do corticosteroids work in terms of general anti-inflammatory activity?
Mimics action of endogenous glucocorticoids
What is the hypothalamic-pituitary-adrenal (HPA) axis?
CRH → ACTH → Cortisol
What are the metabolic effects of corticosteroids?
- ↓ Glucose uptake by fat/muscle
- ↑ Gluconeogenesis
- ↑ Protein catabolism
- ↓ Protein anabolism
What are the anti-inflammatory effects of corticosteroids?
- ↓ Leukocyte chemotaxis
- ↓ Monocyte activity
- ↓ B/T cell proliferation
- ↓ Release of pro-inflammatory factors (e.g. IL-1, TNF…)
- ↓ Eicosanoid production
- ↑ Anti-inflammatory factors (e.g. IL-10, annexin-A1…)
What are the ways in which glucocorticoid receptor (GRα) mediates transcription?
- Binds to glucocorticoid response element (GRE) and stimulates transcription.
- Binds to negative GREs to repress transcription.
- Efficacy of transcription promotion by Fos and Jun binding to AP1 reduced as GRα binds to them.
- Binding to NF-κB reduces transcription promotion by p50 and p65.
What are the non-genomic effects of corticosteroids?
- Inhibition of neutrophil degranulation
- Inhibition of mast cell degranulation
What are the side-effects of corticosteroid use?
- Increased change of opportunistic infections (immunosuppression)
- Impaired wound healing
- Oral thrush
- Osteoporosis
- Hyperglycaemia
- Muscle wasting
- Extreme: Cushings syndrome
What are the consequences of sudden withdrawal of corticosteroid therapy?
- Acute adrenal insufficiency
- Inhibition of HPA axis by negative feedback results in reduction in natural adrenal glucocorticid production
What conditions can be treated with corticosteroids?
- Addison’s disease
- Asthma
- Eczema
- Rheumatoid arthritis
- Anti-rejection
- Reduction of cerebral oedema
What are the characteristcs if asthma?
- Inflammation of airways
- Bronchial hyper-reactivity (hypersensitivity to irritant stimuli)
- Reversible bronchoconstriction
Which immune cell is most important in the pathogenesis fo asthma?
TH2 cells
How do TH2 cells mediate pathogenesis of asthma?
- IL-5: Eosinophil priming
- IL-4 & IL-13: Production of IgE by B cells and expression of FcεR1 by mast cells
What is the role of mast cells in asthma?
- Releases histamine and CysLTs that promote bronchoconstriction (acute phase).
- Release of IL-4, 5 & 13 and TNF that recruit eosinophils and macrophages (late/delayed phase). These cells mediate airway smooth muscle hypertrophy and hypersensitivity of airway epithelium.
Why is salmeterol longer lasting than salbutamol?
Lipophilic tail allows integration into PM that acts as a reservoir
What is chronic obstructive pulmonary disease (COPD)?
Chronic inflammation of airways resulting in narrowing and shortness of breath
