SPR L1 Corticosteroids Flashcards
Learning Outcomes
for general perusal
- Be able to describe how corticosteroids are released and act on cells
- Contrast Gluco versus Mineralocorticoid actions using examples
- Describe the properties of steroids used in the clinic
- Give details of the uses of steroids to treat rheumatoid arthritis and other muscle/bone inflammation
- List the common side-effects of steroids, and the features of Cushing’s syndrome
Control in Endocrine Hormone Systems
- Outline this control
- What happens when you give high doses?
- See picture. Self regulatory system.
- you drive the negative feedback and shut down the production of endogenous steroids
Hypothalamic-Pituitary-Adrenal (HPA) Axis
- What regulates the axis normally?
- What acts as a +ve driver on the hypothalamus?
- What does this cause?
- What gives a negative feedback loop?
- Circadian Rhythm
- StressC
- CRH to act +vely on pituitary, and ACTH to act +vely on the adrenal glands to produce cortisol and give tissue actions
- These tissue actions feedback negatively on the pituitary and the hypothalamus
Adrenocorticotrophic hormone (ACTH, corticotrophin)
- What is this hormone, what is it produced from, and where?
- What is the action of this hormone?
- What are these?
- -39 amino acid hormone generated from POMC in the endocrine pituitary gland
- Stimulates cortisol release of adrenal hormones
- ‘Steroids’ Glucocorticoids - metabolic
Mineralocorticods - electrolyte regulating
Weak androgens - androstenedione
(Pro-opiomelanocortin (POMC) is a precursor polypeptide with 241 amino acid residues)
What is hydrocortisone?
Cortisol
The main glucocorticoid
(cortisone is inactive)
Glucocorticoids versus Mineralocorticoids
- Where are both produced?
- Where do they bind in the body?
- What are glucocorticoids used as?
- What are mineralocorticoids used as?
- Why do glucocorticoids have low activity in the kidney?
- What is Pseudohyperaldosteronism?
- The adrenal cortex. Mineralocorticoids – Zona G
Glucocorticoids – Zona F.
- Glucocorticoid receptor: widely expressed
Mineralocorticoid receptor: mainly expressed in epithelial cells in kidney, colon, bladder
- as anti-inflammatory drugs
- such as aldosterone regulate electrolyte balance in the kidney (e.g. fludrocortisone used in Addison’s disease)
- due to the action of the enzyme 11-b-hydroxysteroid dehydrogenase which inactivates GCs
- Activation of the Mineralocorticoid receptor by GCs
Examples of Steroids
- Give an example of a Glucocorticoid
- Where does it bind?
(endogenous ones in bold)
-
hydrocortisone
- prednisolone, deflazacort
- Betamethasone, dexamethasone (potent)
- Beclomethasone (asthma) - Bind to the Glucocorticoid Receptor in the cytoplasm (widely expressed) Anti-insulin
Examples of Steroids
(endogenous ones in bold)
- Give an example of a Mineralocorticoid?
- Where does it bind?
- What are the actions?
- How can excess MC secretion be managed?
- aldosterone, fludrocortisone (synthetic)
- Bind to the mineralocorticoid receptor expressed mainly in kidney, epithelial cells of colon and bladder, regulate electrolyte balance
- Increased Na+ reabsorption in the distal tubule of the kidney, increased K+ and H+ excretion
- Spironolactone - K+ sparing agent used in CHF
Biosynthesis of corticosteroids and adrenal androgens
- What is the precursor for all three types? (GC, MC and Adrenal Androgens)
- Name an important enzyme involved?
- Cholesterol
- 11-beta hydroxylase
- Where are Steroid hormone receptors found?
- Outline what happens upon binding
- in the cytosol
- receptor changes shape, becomes active, increases transcription of certain genes involved in immune response
Properties of the Glucocorticoid Receptor
- What is the basic structure of the glucocorticoid receptor?
- What is key to function of steroid receptors?
- How does the activated Glucocorticoid Receptor identify its target genes in the nucleus?
1. NH2 - activation domain - DNA binding domain - ligand binding domain - COOH
all steroid receptors consist of modules that perform specific functions
- Dimerisation (binds as a dimer, sits on top of the DNA)
- GC receptor dimers bind to specific hormone response elements (HREs) on target genes.
(Any gene with that sequence will be activated by the gluocortoids. Mutations in any of these will change the specificity of the steroid)
Actions of Glucocorticoids
What are the main actions of glucocorticoids?
Metabolic - hydrocortisone
Anti-inflammatory - prednisolone
Immunosuppressive - dexamethasone
Corticosteroids: Too Little versus Too Much
- What results when there is a deficiency of corticosteroids?
- What results when there is an excess of corticosteroids?
- Addison’s Disease
- Cushing’s Syndrome
Metabolic effects of Glucocorticoids
- What are the main actions?
- What are the actions on the liver?
- What is there a tendancy towards?
- What can long term use lead to?
- protecting glucose-dependent tissues (brain and heart) from starvation => effect carbohydrate and protein metabolism
- decrease glucose uptake and utilization increase gluconeogenesis
- tendency towards hyperglycemia
- Decreased protein synthesis, Increased protein breakdown => muscle (Cushing’s Disease)
- provides amino acids and glycerol for gluconeogenesis
- tendency towards hyperglycemia
- Long-term use can lead to fat redistribution (Cushing’s Syndrome)
Clinical use of Glucocorticoids
Outline the main uses
- Replacement therapy for Addison’s disease (adrenal failure)
- hydrocortisone (GC), fludrocortisone (MC)
- anti-inflammatory/immunosupressive therapy
- prednisolone, dexamethasone
- asthma: beclometasone (inhalation) EOP 2
- eczema
- allergic conjunctivitis
- rhinitis
- autoimmune disease-rheumatoid arthritis, inflammatory bowel disease
- transplant patients to prevent graft v host reactions
- used in CANCER
- combination with cytotoxic drugs e.g. Hodkins, leukemia
- reduce cerebral oedema in patients with brain tumor (dex)
- anti-emetic therapy in conjunction with chemotherapy
- weight gain to stimulate appetite (cachexia)