Lecture 4 Flashcards
Corticosteroids
Suppress the IR by mimicking the action of endogenous glucocorticoids
the term corticosteroids includes both endogenous glucocorticoids and artificial steroids (e.g. prednisolone)
Neg feedback in HPA axis
Short feedback loop from ACTH (from pituitary) to the hypothalamus
Long feedback loop from glucocorticoids acting on both the pituitary and the hypothalamus
Ani-inflammatory actions of corticosteroids `
- reduced activity of leukocytes
- reduced activity of monocytes
- reduced clonal expansion of T/B cells
- reduced pro-inflammatory cytokine production
- reduced eicosanoid production
- increased release of anti-inflammatory factors
Corticosteroid mechanism of action
- Bind glucocorticoid receptor (GRα) present as homomers in the cytoplasm bound to hsp90
- binding of ligand to receptor induces dissociation from Hsp90 and dimerization of GRα receptors
- translocation to nucleus to either transactivate or transrepress a wide range of genes (up to 1% of the total genome)
What are the 4 ways in which ligand bound GRα can regulate gene expression
1) GRα binds a positive glucocorticoid response element (GRE) within a promoter region for a gene with low transcriptional activity and activates transcriptional machinery (TM)
2) The TM is constitutively driven by transcription factors (TF) and GRα binds to negative GREs causing TF displacement and repression
3) The TM is driven at a high level by fos/jun TFs binding to their AP-1 regulatory site - the effect of which is reduced by GRα binding
4) prior GRα binding prevents the TFs p65 and p50 binding to the NF-KB site, therefore reducing TM activity
Non-genomic actions of corticosteroids
- Hydrocortisone inhibits neutrophil degranulation (this is not prevented by either GRα antagonists nor by inhibitors of translation)
- Inhibits degranulation of mast cells (membrane impermeable and membrane permeable corticosteroids have identical effects i.e. binding to intracellular GRα not required)
- i.v betamethasone significantly reduced pollen induced nasal irritation. (occurred within 10 mins - too fast for genomic effect)
Side effects of corticosteroids
- opportunistic infection
- thinning of skin and impaired wound healing
- oral thrush (candidiasis)
- osteoporosis (inc osteoclast/dec osteoblast)
- hyperglycaemia
- muscle wasting
- stomach ulceration
- avascular necrosis of femoral head
- reduced sleep and psychosis
How are the side effects of steroid treatment limited?
- co-prescribe
- low doses for minimal amount of time
- give locally
Cushing’s syndrome
Can occur from long term steroid use
symptoms include: pot bellied appearance, hair loss (primarily body, not face and legs), polydipsia and polyuria
Why should patients not suddenly withdraw from length steroid therapy (>1-2 weeks) ?
Acute adrenal insufficiency as the patient fails to resynthesise enough steroids
Withdrawal should be tapered to enable full HPA recovery and is often patient specific
Name 2 different corticosteroids with very different potencies and duration of action
- Hydrocortisone (cortisol used therapeutically). Short acting (<24hrs)
- Dexamethasone - given via iv for treating swelling and inflammation in metastatic cancer
When are corticosteroids prescribed?
- Asthma (inhalation)
- Eczema (1% hydrocortisone topical cream)
- Autoimmune conditions
- To reduce brain tumour/high altitude cerebral oedema
- Addison’s disease where adrenal glands produce insufficient glucocorticoids
Cellular response to asthma
Mainly Th2
Dendritic cell presentation of allergen and presentation to CD4+ T cell leading to Th0 and Th2
Th2 releases:
- IL-5 (eosinophil priming)
- IL-4 and IL-13 (IgE production by B cells and plasma cells and induces FcεR1 expression in mast cells and eosinophils
high circulating IgE levels also increase mast cell FcεR1 expression
FcεR1 crosslinking
Allergen induced FcεR1 crosslinking on mast cells leads to degranulation and histamine and CysLT release (bronchoconstriction and vasodilatation)
Mast cells also release cytokines that recruit macrophages and eosinophils for delayed/late phase
In late phase the epithelium is damaged by release of granule proteins such as eosinophil cationic protein and eosinophil major basic protein which leads to airway hypersensitivity
more nociceptive C fibres accessible to irritant stimuli
Which patients are recommended prophylactic asthma therapy
Those who suffer asthmatic symptoms or use a bronchodilator >2x per week or wakes up once a week with asthmatic symptoms
Stepwise approach to asthma treatment
1) short acting inhaled B2 adrenoceptor agonist e.g. SALBUTAMOL
2) regular inhaled corticosteroid e.g. BECLOMETHASONE
3) Long acting inhaled B2 agonist (LABA) e.g. FORMOTEROL
4) addition of either:
- leukotriene receptor antagonist e.g. MONTELUKAST
- THEOPHYLLINE
- oral LABA
5) daily oral corticosteroids at a low dose
Each drug is added sequentially alongside the previous
B2 agonists in asthma treatment - mechanism
Act as Gs coupled B2 receptors in bronchial smooth muscle to induce relaxation and bronchodilatation
AC, cAMP, PKA phos of MLCK to inactivate. cAMP also inhibits mast cell degranulation
- salbutamol works within 30mins lasting 3-5hr
- formoterol used prophylactically. duration of action 8-12hrs. Longer action due to lipophilic tail which incorporates into the PM and acts as a drug reservoir. (lipophilic tail also contains another binding site for the B2 receptor)
Side effects of B2 agonists in asthma
Tremor (excitation of B2 in skeletal musc)
Tachycardia (excitation of facilitatory B2Rs in cardiac noradrenergic terminals
Beclomethasone
Inhaled corticosteroid used prophylactically
suppresses inflammation. Often used in combo with formoterol in the same inhaler to increase compliance.
Slow onset as genomic effect takes time
Delivery directly to lungs reduces systemic exposure thus limiting side effects but oral thrush can still occur
Theophylline in asthma treatment
PDE inhibitor, inc cAMP/PKA for bronchodilatation and mast cell stabilisation
- Prophylactically, not advised for acute attacks
- cardiovasc side effects eg tachycardia
- metabolised by CYP450 so caution advised in polypharmacy
Montelukast
CysLT antagonist
Can induce bronchodilatation (less effective than salbutamol)
Used prophylactically if B2 and steroid therapy are insufficient
Ipratropium
Inhibits M3 receptors on smooth muscle to induce bronchodilatation
- short acting, non-selective muscarinic receptor antagonist
- used more in COPD than asthma
Sodium cromoglycate
Mast cell stabiliser
Used prophylactically in cases where mast cells are key players in pathology
Omalizumab
Humanised mAB against IgE
Recommended in specialist centres for patients with severe, persistent allergic asthma refractory to LABAs and corticosteroids
Binds to Cε3 region of IgE (part of heavy chain that binds FcεR1) to inhibit allergen induced mast cell degranulation
omalizumab built on IgE framework so does not activate the FcεR1 itself
Given as an injection every 2-4 weeks
Immune cells involved in the pathology of asthma and COPD
Asthma = eosinophils and mast cells
COPD = macrophages and neutrophils
Characteristics of COPD
Fibroblast proliferation/fibrosis of the airways (underlies irreversible narrowing)
Alveolar tissue destruction
Epithelial cell proliferation (in contrast to epithelial loss in asthma)
Short acting bronchodilators in COPD treatment
Not particularly effective due to the limited reversible nature of narrowing in COPD as fibrosis reduces elasticity
May be used in acute exacerbations
LABA-LAMA combination inhalers in COPD
LABAs eg formoterol and indacterol used in combo with LAMAs (muscarinic antagonists) eg tiotropium (not short acting ipratropium)
LABA = MLCK phosphorylation and inactivation
LAMA = M3 inhibition = inhibition of PLC and IP3
Corticosteroid use in COPD
Largely ineffective but may be used in acute exacerbation e.g. when there is a co-existent infection or where small airway inflammation is predominant
Reduced efficacy may be due to reduced histone deacetylase 2 (HDAC2)
O2- and NO from cigarettes and immune cells lead to the formation of peroxynitrate (ONOO-) which nitrates HDAC2 at the active site leading to inactivation, ubiquitination and degradation.
Reduced HDAC2 = more acetylation of GRa which prevents inhibition of NF-KB driven inflammation
Theophylline
cAMP in smooth muscle = bronchodilatation
cAMP in immune cells = reduced chemotaxis and activation
Roflumilast
Selective PDE1V inhibitor (main PDE in neutrophils, Tcells and macrophages)
Used as an add on to LABAs
Other future options for COPD treatment
CXCR2 antagonists to reduce neutrophil chemotaxis
Anti-fibrotic therapy
Inhibition of elastase activity (likely contributes to development of emphysema)
Most effective treatment for COPD
Oxygen
