Glucocorticoids and Mineralocorticoids Flashcards
2 Main parts of Adrenal Gland and the substances they produce
Adrenal Cortex = Corticosteroids
Adrenal Medulla = Catecholamines
3 Main types of Corticosteroids, their site of production and their stucture
Mnemonic: MGA GFR (outer to inner).
From outer to inner layer:
Zona Glomerulosa - Mineralocorticoids (21 C)
Zona Fasciculata - Glucocorticoids (21 C)
Zona Reticularis - Androgens (19 C)
What are the fight or flight hormones?
Adrenal Medula secretion –> Catecholamines:
Epinephrine/ Adrenaline
Norepinephrine/Noradrenaline
What is the precursor of all steroid hormones, glucocorticoids, mineralocorticoids and sex hormones?
Cholesterol!
All the products derived from cholesterol are steroids (T/F)
T. Pero preferred lang tawagin na cortisol at glucocorticoid
Mineralocorticoids:
What is the Major mineralocorticoid produced? Function?
Aldosterone.
Acts on the DISTAL PORTION of convoluted tubule to promote Na reabsorption and K excretion.
Basta MINERALocorticoid = aldosterone = Na and K (Mineral —> ions …ewan, basta)
What controls secretion of aldosterone?
Primarily: RAAS
Secondary: ACTH
Mineralocortioid Receptor is highly specific. (T/F)
F. It can also bind with glucocorticoids (ex. cortisol)
Why? Since Mineralo- and Gluco- are higly similar in structure.
When administering doses of cortisol, its possible to observe hypertension and hypokalemia. (T/F)
T.
Hypertension and hypokalemia is caused by high doses of aldosterone which is almost similar, in structure, to cortisol
Blood levels of Cortisol is 2000x higher than Aldosterone. How can aldosterone stimulate SPECIFIC biological effects?
Target cells for aldosterone has an enzyme which can target cortisol and convert it into cortisone (has lesser affinity to Mineralo- Receptor). With this, aldosterone can now easily bind to Mineralo- Receptor
Mineralocorticoids:
What are its effects on the body?
[Think about Na+ and K+]
[Na+] Sodium Retention —> leads to hypertension, edema and heart failure
[K+] Potassium Excretion —> Hypokalemia —> leads to muscle weakness and metabolic alkalosis.
FLUDROCORTISONE is a distinct mineralocorticoid agonist only for mineralocorticoid receptors. (T/F)
F.
FIRST, it is a actually a glucocorticoid.
It has glucocorticoid activity when given at high concentrations and mineralocorticoid activity at low concentrations.
At what dose should you administer Fludrocortisone for it to exhibit a salt-retaining activity (bale mineralocorticoid activity)? Does this dose have significant anti-inflamm effects?
0.1 mg given 2-7 times per week.
The dosage is too small to have significant inflammatory effects.
Glucocorticoids Characteristics:
When does blood conc of glucocorticoids increase?
During stress (mental, emotional, etc)
Glucocorticoids Characteristics:
Do glucocorticoids have immunosuppressive, metabolic and anti-inflammatory effects?
Yes. For metabolic, the inc. glycogenolysis, gluconeogenesis, proteolysis and lipolysis.
They also reduce the activity of the innate and acquired immune systems.
Glucocorticoids Characteristics:
What is the Permissive Effect?
Catecholamines causes vasoconstriction. The presence of glucocorticoids further enhance the vasoconstrictive effects of catecholamine such that it can reverse hypotension.
Glucocorticoids Characteristics:
What is the main endogenous glucocorticoid? How much of it is physiologically secreted by the body per day?
Cortisol (a.k.a. Hydrocortisone)
~20mg/day (15-30mg/day)
Glucocorticoids Characteristics:
Describe the chain of events that lead to cortisol production.
Stress —> stimulate Hypothalamus to secrete Corticotropin releasing hormone —> signals Ant. Pituitary gland to release Adrenocorticotropic Hormone —> tells adrenal gland to secrete cortisol
Glucocorticoids Characteristics:
When are cortisol levels highest? lowest?
Highest in the morning (give you enough energy to start the day).
Lowest at midnight.
Glucocorticoids Characteristics:
What are the carrier proteins of cortisol?
- Transcortin (main)
2. Albumin
Glucocorticoids Characteristics:
Name the 2 hormones that affect the binding of Cortisol to its carrier proteins? What are their effects?
- Estrogen: causes the inc. in serum conc. of transcortin thus inc. the total amount of cortisol WITHOUT changing the level of free cortisol
- Progesterone: has great affinity for transcortin and can displace bound cortisol resulting into an inc. in active free cortisol
Glucocorticoids Characteristics:
Name 2 states wherein there is an increase in the level of binding proteins in the serum.
- Pregnancy (due to inc. in estrogen)
2. Hyperthyroidism
Glucocorticoids Characteristics:
Name 2 factors that regulate ACTH secretion.
- Free cortisol inhibits ACTH (negative feedback)
2. CRH secreted by Hypothalamus promote ACTH secretion by ant. pituitary gland.
Glucocorticoids Characteristics:
What is the plasma half life of cortisol?
80 minutes
Glucocorticoids Characteristics:
There are 2 types of negative feedback mechanism that stops cortisol production. What are they?
- Short loop mechanism: free cortisol signals Ant. Pituitary gland to stop ACTH production
- Long loop mechanism: free cortisol signals the hypothalamus to stop CRH production
Glucocorticoids Characteristics:
Describe the general mechanism of glucocorticoid receptor regulation.
Ligand enter cell —> bind to cytoplasmic receptor —> receptor dissociates from HSP90 —> ligand-receptor complex transported into the nucleus —> interacts with DNA and nuclear proteins —> mRNA transcription —> mRNA transported to cytoplasm —> cellular changes
Glucocorticoids Characteristics:
What are the 2 genes of glucocorticoid receptor?
- hGR-alpha
2 hGR-beta
How does INFLAMMATION and STEROIDS affect chromatic structure?
Inflammation —> Histone acetylation —> transcriptional activation
Steroids —> Histone deacetylation —> gene silencing
Glucocorticoids Characteristics:
It is one of the famous secondary messengers of the anti-inflammatory action of glucocorticoid.
Lipocortin-1
Effects of Glucocorticoids:
What are the main effects of glucocorticoids?
(1) Metabolic, (2) Skeletal, (3) Fat cell, (4) Connective tissue and bone, (5) Anti-inflammatory effects
Metabolic Effects: Inc or Dec?
- Glycogenolysis? Gluconeogenesis?
- Protein synthesis?
- Lipolysis
- Osteoclast activity? Osteoblast?
- Vit D?
- Inc, Inc - results in hyperglycemia
- Dec -results in muscle weakness & atrophy
- Inc - lipolysis and fat redistribution (Cushing)
- Inc, Dec. - results in osteoporosis
- Dec conversion of Vit D2 to active vit. D -resuts in dec. Ca2+ absorption from GIT
Skeletal Effects:
- Muscles mass (Inc or Dec?)
- Protein catabolism is greatest for the _____ derivatives.
- It will dec. due to decreased protein synthesis
2. Fluorinated derivatives
Fat Cell Effects:
- Synthesis of Long chain FA (inc or dec?)
- Stimulate the effects of what lipolytic hormones?
- dec or inhibited
2. catecholamins, glucagon, GH
Connective Tissue & Bone effects: (inc/dec?)
- Bone formation?
- Ca2+ absorption
- Parathyroid hormone (PTH) secretion?
- Bone resorption and remodeling?
- dec
- dec
- inc, due to decreased plasma levels of Ca2+ (compensartory mechanism)
- Inc, due to release of PTH
All of the 4 Factors lead to OSTEOPOROSIS
Anti-inflammatory Effects:
What are the 3 Major Mechanisms?
- Interference w/ Leukocyte Migration
- Inhibition of Arachidonic acid cascade
- Permissive effect o catecholamine activity
Anti-inflammatory Effects:
Inhibition of Arachidonic acid cascade results into?
decreased production of Prostaglandins, Interleukins and Cytokines
These are derived from the degradation of Arachidonic acid due to the action of Phospholipase 2
Anti-inflammatory Effects:
What are the cellular changes that are involved?
- Dec.in prolif and migration of Agranulocytes
- Reduced number of Eosinophils and Basophils
- Neutrophils INCREASE in number
Glucocorticoids can be used in Therapy. Give some examples of diseases in these areas that could be managed by cortisol: 1. Dermatologic 2. Allergic disease 3. Rheumatologic 4. Asthma
- Atopic Dermatitis. Eczema
- allergic rhinitis, urticaria
- Systemic Lupus Erythematosus
Glucocorticoids could serve as a replacement therapy in Adrenal Insufficiency.
Describe how is this possible.
- Post adrenalectomy,
- Hypopituitarism,
- Withdraw of prolonged drug use
Glucocoricoids can be divided into classes using what factors/characteristics?
- Potencies in Na+ retention
- effect on Carb metabolism
- Anti-inflammatory effects
Structure-Activity Relationship:
- Effect of C6 methylation?
- Effect of C9 Fluorination?
- Inc in anti-inflamm. activity and improves pulmonary penetration (ex. methylprednisolone)
- Inc anti-inflamm effect w/ pronounced catabolic effect. (ex. dexamethasone)
Commonly Used Glucocorticoids:
Give examples of 2 short-acting drugs.
When are they used?
Hydrocortisone and Cortisone.
- potencies are close to the normal endogenous cortisol of the body
- HIGH MINERALOID potencies.
- used during shock because it can raise BP
Commonly Used Glucocorticoids:
Give examples of 4 intermediate acting drugs. What are their characteristics?
Methylprednisolone, Prednisone, Prednisolone, Triamcinolone.
- high anti-inflamm potency
- low mineralocorticoid potency
Commonly Used Glucocorticoids:
Give 2 examples of Long acting drugs. What are their characteristics?
Betamethasone and Dexamethasone
- they are fluorinated
- very high anti inflamm potency
- very low mineralocorticoid potency
- causes the GREATEST effect on glucose Metab
Adverse effects:
At what dose will the use of glucocorticoid for more than 1 week result into HPA axis suppression?
What are its know adverse effects?
7.5 mg Causes Cushing syndrome (persistent lipolysis) Suppressed Immune system Peptic Ulcer Growth suppression, Osteoporosis.
Should nasal steroid be lipophilic or hydrophilic?
Lipophilic
Faster uptake by nasal mucosa
Greater retention within the tissue
Enhanced glucocoricoid receptor binding