Corticosteroids Flashcards
What are the two parts of the Adrenal Gland
Medulla
Cortext
What is the adrenal gland
Apex of kidney
What does the medulla produce
Adrenaline
Catecholamine / amino acid hormone
What does the cortex produce
Steroid hormones
Layers of the Cortex
Zona Glomerulosa
Zona Fasciculata
Zona Reticularis
Mineralocorticoids
- Function
- Example
- Produced Where
Mediate Salt balance
Ex. Aldosterone
Produced by Zona Glomerulosa
Glucocorticoids
- Function
- Example
- Produced Where
Metabolic (how body uses sugars) and immune effects
Ex. Cortisol
Zona Fasciculata
Androgens
- Function
- Example
- Produced Where
Precursors for strong androgens
Responsible for sex hormones like
Testosterone and
Estrogens
Ex. DHEA
Zona Retucularis
What does HPA Axis control
Cortisol release from Zona Fasciculata
Describe main pathway of HPA Axis
Hypothalamus controls synthesis of Corticotropin Releasing Factors (CRF/CRH), hormones which controls ACTH production by the anterior pituitary
ACTH (Anterior Pituitary) stimulates steroid production, cortisol in synthesized in the adrenal cortex
Describe Negative Feedback in the HPA Axis
Cortisol has a negative feedback on
CRH production (Hypothalamus)
ACTH (Anterior Pituitary)
Why is cortisol important
Suppresses stress response and acts on glucocorticoid tissues, catabolism, and immuno surpression
Lack of cortisol can causes hyperproduction of certain products
What is Aldosterone
Mineralocorticoid Response
Targets kidneys promoting Na+/Water reabsorption and K+ excretion
Increases blood volume and pressure
Describe the generalized mechanism of steroid hormone action
Steroid hormone diffuses into plasma membrane
Cytoplasmic unliganded receptor forms a complex with Hsp90
Hormone binds to cytoplasmic receptor, dissociates from Hsp
Forms a Steroid-receptor dimer (activated state)
Dimerized receptors interact with DNA and influence transcription of target genes: Glucocorticoid receptors
Define spectrum in the context of steroids
Drugs can be designed to have different affinities for Glucocorticoid receptors or Mineralocorticoids receptors
What are glucocorticoid target tissues
Adipose (body fat), muscle, liver
What kind of steroid do glucocorticoid target tissues express
11beta-hydroxysteroid dehydrogenase, type 1
What does 11beta-hydroxysteroid dehydrogenase, type 1 do?
Activates Cortisol
Converts cortisone to Cortisol (Type 1)
Ketone to Alcohol group
What causes corticosteroid specificity
Affinity of compound/receptor and metabolism in target tissues
Prednisone
Prodrug
Orally taken and metabolized to prednisolone in the liver and in important glucocorticoid target tissues
Prednisolone
Strong topical effect (applied on skin)
Active form of prednisone
What does cortisol activate
Glucocorticoid receptors
Mineralocorticoid receptors
What weak effect does cortisol have
Weak mineralocorticoid effects in vivo
What does 11beta-hydroxysteroid dehydrogenase, type 2 do?
Inactivates Cortisol
Converts Cortisol to Cortisone
Alcohol to Ketone group
What is Pseudohyperaldosteronism
Excess cortisol can have an effect on aldosterone target tissues (kindeys), increasing blood pressure through water/Na+ reabsorption
Licorice contains an inhibitor of 11beta-hydroxysteroid dehydrogenase, type 2. Preventing inactivation of cortisol
How does Pseudohyperaldosteronism occur
Licorice contains an inhibitor of 11beta-hydroxysteroid dehydrogenase, type 2. Preventing inactivation of cortisol
What is Apparent Minceralocorticoid Exess
Looks like an excess of mineralocorticoid but isn’t
Caused by mutations to 11beta hydroxysteroid dehydrogenase, type 2 gene
Inhibits conversion of cortisol to cortisone
Cortisol then acts act aldosterone tissue
Glucocorticoid effect on Carbohydrate Metabolism
Increases circulating glucose
Effect of Glucocorticoid on Fat/Lipid Balance
Catabolic breakdown of fat
Loss of muscle and bone mass in limbs
Fat accumulation in viscera and trunk
(Skinny Fat)
Describe pathway of glucocorticoid effects (Initial)
Food is consumed, calories are transferred to selected sites (Adipose Tissues)
Adipose Tissues: Triglycerides are broken down by lipolytic hormones into free fatty acids
(Short term loss of fat)
(High insulin from desensitization to glucose spike)
Describe pathway of glucocorticoid effects (Liver)
Glucose inhibits insulin production in muscles
Muscle proteins are broken down to form amino acids which are carried to the liver to be used as glucose precursors
Glucose is formed and is used to inhibit insulin in adipose tissue
Cyclooxygenase-2 function and role
COX-2 is an inflammatory mediator
Arachidonic acid conversion to different prostanoids depending on cell type (Prostaglandins and Thromboxane)
Glucocorticoids relationship with COX-2
Glucocorticoids suppress transcription of the COX-2 gene
What are the effects of inhibiting COX-2
Affects all downstream products like
PGI2,TXA2
PGF2, PGD2, PGE2
What is Annexin A1
Lipocortin/Annexin with very powerful and broad anti-inflammatory effects
Effects are very early in inflammatory response
What are the two effects of Annexin A1
- Directly effecting Leukocytes and inhibiting their ability to infiltrate tissue
- Suppressing phospholipase A2 activity, prevents formation of arachidonic acid, thus, preventing all downstream prostanoids
What is Addison’s Disease
Symptoms
Insufficient glucocorticoid production (and often mineralocorticoids)
Lack of glucose causes fatigue, salt + sugar balance issues, skin discolouration
How is Addison’s Disease treated
Hydrocortisone
Glucocorticoid / Mineralocorticoid
supplements can treat hormone deficiency
What is Cushing’s Syndrome
Symptoms
Excessive cortisol from adrenal overactivity
Round face and fat deposition in trunk
Muscle loss and osteoporosis (Protein and bone catabolism)
Resembles side effects of therapeutic doses of GCs
What causes Cushing’s Syndrome
Adrenal Tumours (Produces cortisol)
Pituitary Tumours (Produces ACTH, stimulates adrenal cortex)
Drug-Induced (High dose GC)
Ectopic Tumour (Produces ACTH, stimulate adrenal cortex)
How is Cushing’s Syndrome treated
Resection of adrenal / pituitary tumours
Adjustment of doses of cortisol
Side Effects of Synthetic Glucocorticoids
Metabolic: Glucose produces high blood sugar - Hyperglycemia
Immunosuppressive
Catabolic: Osteoporosis, muscle wasting
Anti-Inflammatory: Affects cell division, slow wound healing, ulcerations
Hypertension caused by non-specific MC effects of GCs
Psychosis: Especially in elderly
Why should Glucocorticoid treatments not be stopped abruptly
GC acts as cortisol and negatively inhibits ACTH and CRH production. Body grows dependent on GC and can’t make its own cortisol
Body needs time to synthesize its own cortisol
Effects of abruptly stopping GC treatment
Addisonian Crisis:
Hypoglycemia (Low Glucose)
Hyponatremia (Low Sodium)
Hyperkalemia (High Potassium)
What is Tapering Treatment
Slowly reducing a treatment to prevent an abrupt stop
Used in stopping long term glucocorticoid
treatments
