ELM 17: Asthma 2 Flashcards
What are nuclear hormone receptors?
48 in humans
Intracellular
Bind lipid soluble ligands
When activated bind to DNA and increase or decrease transcription of specific genes
What is an example of a nuclear hormone receptor in relation to asthma?
Glucocorticoid and mineralcorticoid receptors
What is the overall structure of nuclear hormone receptors?
Sequence is divided into regions
- N terminal with loosely folded region
- Then DNA binding domain
- Then hinge region
- Then ligand binding domain
- Then C terminal domain
What is the basic mechanism of glucocorticoid receptors?
- Steroid hormone passes through membrane and interacts with glucocorticoid receptors
- Attaches heat shock proteins dissociate
- Receptors dimerise and enter nucleus via nuclear pore
What is transactivation?
- After entering nucleus NHR dimer binds to hormone responsive element
- Recruits coactivator proteins and RNA polymerase
- Promotes transcription of mRNA and protein expression
What is transrepression?
- NHR binds to transcription factor and inhibits transcription
- Involves receptor monomers instead of receptor binding to DNA
What are the two actions of adrenal steroids?
Glucocorticoid
Mineralcorticoid
What are the effects of glucocorticoids?
Metabolic effects
Anti inflammatory
Immunosuppressive
What are the effects of mineral corticoids?
Water and electrolyte balance
What are two different types of natural steroids and what is the difference in their activities?
Cortisol/corticosterone which acts on both GCRs and MCRs
Aldosterone which acts on MCRs only
What is Cushing’s syndrome?
Caused by excess glucocorticoids
- Increased abdominal fat
- Hypertension
- Muscle wasting
- Osteoporosis
- Poor wound healing
- Thinning of skin
Why is transrepression more favourable than transactivation?
Both have anti-inflammatory effects but transrepression has less side effects
What are SEGRAMS?
Selective glucocorticoid receptor agonist/modulator
- Favours the transrepression pathway
- Should have more favourable side effect profile
What is the Hypothalamic Pituitary Adrenal Axis?
Hypothalamus releases corticotrophin releasing factor
Triggers the pituitary gland to release adrenocorticotrophic hormone
Triggers adrenal cortex to release hydrocortisone
Hydrocortisone increases availability of glucose and suppresses immune system to prepare body for fight or flight
What are leukotriene receptor antagonists?
Block leukotrienes that contract bronchial smooth muscle, stimulate mucus secretion and increase microvascular permeability
How are leukotriene receptor antagonists administered?
Orally through drugs
Add on treatments
What are some side effects of leukotriene receptor antagonists?
GI tract problems and abdominal pain
Headaches
Rarely psychiatric side effects like hallucinations
What are muscarinic receptor antagonists?
Inhibit receptors that cause bronchoconstriction and mucus production
What are some side effects of muscarinic antagonists?
Dry mouth
Constipation
Headache
Nausea
Dizziness
Cardiac Arrhythmias
What are two examples of muscarinic antagonists used for asthma>
Ipratropium bromide (SAMA)
Tiotropium bromide (LAMA)
What is the mechanism of theophylline?
Non selective inhibitor of phosphodiesterases, can promote bronchodilation and reduce inflammation
Antagonist of adenosine receptors, can promote bronchodilation
What are some side effects of theophylline?
Nausea and vomiting
Anxiety
Headache
Sleep disturbances
Tachycardia and other dysrhythmias
Convulsions
What is Omalizumab?
Humanised monoclonal antibody against immunoglobulin E(IgE)
Binds to IgE and rapidly removes it from circulation
This means its a preventer drug for allergic asthma
