78 Flashcards
Effects of glucocorticoids on asthma
Decreases inflammatory cell number and activation.
Decreases probability and severity of episode of asthma
Things that glucocorticoids suppress in inflam response 1 2 3 4
1) Activity, recruitment and survival of eosinophils, T cells
2) Activation of mast cell cytokine production
3) Macrophage cytokine production, proliferation
4) Cytokine and collagen production by smooth muscle and fibroblasts
Mechanism of glucocorticoid receptor stimulation 1 2 3 4
1) Glucocortiocid enters cell
2) Binds glucocorticoid receptor, receptor dimerises
3) Binding of glucocorticoid removes inhibitory proteins from receptor, exposing nuclear localisation sequence
4) GLC/R complex enters nucleus, binds to glucocorticoid response element to stimulate or inhibit transcription.
Types of glucocorticoid receptors
Positive and negative
Examples of positively-regulated GREs
Glucocorticoid-induced leucine zipper
MAPK phosphatase-1
Inhibitor of xBa
GRE = glucocorticoid response element
Examples of negatively-regulated GREs 1 2 3 4
Through inhibiting NFkB response element, inhibits production/release of: IL-8 COX-2 ICAM-1 NOS2
IKK
I kappa kinase
IKK role
Phosphorylates IkappaBalpha, which results in ubiquitination of IkBa.
IkBa degraded in proteosome because of ubiquitination.
Protein that inhibits NFkB within a cell
GILZ (Glucocorticoid-induced leucine zipper)
How is IKK induced?
Cytokine receptor bound by ligand
Induction of AP-1
1
2
3
1) Cytokine receptor bound, Jun-kinase phosphorylated.
2) Kun kianse phosphorylates Jun.
3) Jun-P and Fos are subunits of AP-1, which then goes to the nucleus, binds to TRE, acts as a transcription regulator
IkBa
Bound to NFkB, prevents NFkB from entering nucleus.
Mechanism by which steroids lead to cellular changes
Transactivation
When are inhaled GCS indicated?
If beta2 agonist needed over 3 times per week (mild persistent asthma)
Examples of inhaled GCS available in combination with beta2 agonists
Budesoinde
Fluticasone propionate
Dose prescription strategy for inhaled GCS
Start at an effective dose and decrease over time (step down slowly, as onset is slow and offset from decreasing dose is slow)
Example of a systemic oral steroid prescribed for asthma
Prednisolone
Example of a GCS used to control severe asthma, not to prevent
Oral prednisolone.
For several days for severe asthma.
Chronically for severe asthma only
Effect of GCS on peak expiratory flow over time
For first week of treatment very wide difference between possible peak expiratory flows. As time goes on, peak expiratory flow increases on average by a low
Adverse effects of inhaled GCS
1
2
3
1) Dysphonia (change in voice)
2) Oral candidiasis
3) Decrease in serum cortisol (not clinically significant)
Adverse effects of oral GCS 1 2 3 4 5 6
1) Osteoporosis
2) Diabetes (stimulates gluconeogenesis enzymes in the liver, increasing blood glucose)
3) Muscle wasting
4) Hypertension
5) Growth suppression (so use cautiously in children)
6) Suppression of adrenal/pituitary/hypothalamic axis
Protocol for taking a patient off oral GCS therapy
Need to wean off chronic use to avoid “withdrawal”
Regulation of endogenous GCS
Cortisol negatively regulates release of GCS from adrenal gland.
Cortisol levels detected by anterior pituitary gland, which releases corticotropin.
Corticotropin negatively regulates adrenal gland release of GCS
Why does chronic oral GCS use lead to withdrawl?
Exogenous GCS negatively regulates GCS release from adrenal gland, causing atrophy.
Methylxantines mechanism of action in asthma.
Not really known.
Has phosphodiesterase activity, decreases cAMP in smooth muscle leading to relaxation.
HDAC2 activation.
Dose limiting side effects of methylxanthines and phosphodiesterase inhibitors 1 2 3 4
Nausea
Vomiting
CNS stimulation (low safety margin)
Cardiostimulation (dysrhythmias)
Example of a selective phosphodiesterase inhibitor
Roflumilast
Roflumilast compared to other phosphodiesterase inhibitors
Reduced incidence and severity of side effects with compared to theophyline
Drug for intermittent asthma (up to 100% FEV1)
SABA
Drug for mild persistent daily asthma (under 80% predicted FEV1)
SABA + daily inhaled GCS
Drugs for moderate persistent daily asthma (50%-80% predicted FEV1)
SABA, daily inhaled GCS and LABA
Drugs for severe persistent asthma (50%-80% predicted FEV1)
SABA, increased daily inhaled GCS dose, LABA, if needed theophylline-SR and anti-leukotrienes and oral GCS
Drugs for very severe asthma (under 50% predicted FEV1)
Oral prednisolone
What are long-acting beta2 agonists always prescribed with?
GCS, SABA
Risk factors for COPD 1 2 a b c d
1) Genes
2) Exposure to particles
a Tobacco smoke
b Occupational dusts, organic or inorganic
c Indoor air pollution from heating and cooking with biomass in poorly-ventilated areas
d Outdoor air pollution
Effect of lung development on COPD
The less the lungs develop, the less ventilation you can get. This increases risk of COPD
Type of lung disease that COPD is
Obstructive
Appearance of obstructive lung disease compared to predicted FEV1
Much less steep FEV1 on graph, lower FVC
Definition of COPD 1 2 3 4 5
1) Preventable, treatable disesae with significant extrapulmonary effects
2) Airflow limitation that is not fully reversible
3) Progressive, airflow limitation associated with abnormal inflammatory response of the lung to noxious particles or gasses
4) Loss of lung parenchyma, small airways.
5) Inflammation, fibrosis, thickening of airways, pulmonary hypertension
Decline of lung function with age
FEV1 decreases over time, to about ~75% of level at 25yo by 75yo
Why don’t GCS work well in COPD?
Different inflammatory effectors than to asthma.
Inflammatory effectors are less sensitive than those in asthma (eosinophils, mast cells are sensitive)
Effect of LABA and SABA on COPD
No effect
Effect of GCS on COPD
Limited effect.
Used because there isn’t really another treatment
