Action of the adrenal Steroids and treatment of adrenal disorders Flashcards
What is the origin of the adrenal medulla?
Neural crest
What is secreted by the adrenal medulla?
Catecholamines
What is the origin of the adrenal cortex?
Mesoderm
What is secreted by the zona glomerulosa and what regulates?
- Mineralocorticoids
* Regulated by ACTH, K+ and renin angiotensin II
What is secreted by zona fasciculate and what regulates
- Mainly glucocorticoids (cortisol and corticosterone)
* Regulated by ACTH
What is secreted by the zona reticular and what regulates?
- Mainly androgens
* Regulated by ACTH and unknown precursors
What is the main mineralocorticoid?
Aldosterone
What is the general role of mineralocorticoids?
Regulate salt/electrolyte and water balance
What are glucocorticoids used for therapeutically?
- Replacement therapy
- Anti-inflammatory
- Immunosuppressive
Describe the regulation of adrenal corticosteroids
- Adrenals are part of the HPA axis
- CRF and ADH act on corticotrophins in the anterior pituitary inducing ACTH release
- ACTH stimulates the synthesis and secretion of both glucocorticoids and mineralocorticoids from the adrenal cortex
- The renin angiotensin system aids ACTH to promote mineralocorticoid secretion
Tetracosactide
Synthetic ACTH analogue (increases stimulation of the adrenal cortex)
Fludrocortisone
• Mimics mineralocorticoid effects
Prednisolone
• Mimics glucocorticoid effects
How can you test to see if there is a primary or a secondary adrenal insufficiency
- Give tetracosactide (ACTH analogue)
- If there is a problem with the pituitary or hypothalamus, the adrenal cortex should still work and hydrocortisone should be produced and detected
- If no hydrocortisone can be detected primary
What is the rate limiting step in the biosynthesis of corticosteroid and mineralocorticoids and sex hormones
- Conversion of cholesterol to pregnenolone
* Regulated by ACTH (and Angiotensin II)
Amioglutethimide
- Inhibits the rate limiting step
* blocks the conversion of cholesterol to pregnenolone
Trilostane
- Blocks 3 beta dyhd
- Used to treat bushings and primary hyperaldosteronism
- Prevents pregnenolone -> progesterone
- Prevents 17a-OH-pregnenolone -> 17a-OH-progesterone
- Prevents Dehydroepiandosterone -> androstenedione (sex hormone pathway)
Metapyrone
- Blocks 11B-OH: stops the beta hydroxylation of C11
- Stops progesterone -> corticosterone
- Stops 17a-OH-progesterone ->hydrocortisone
Carbenoxolone
- Inhibits the conversion of hydrocortisone to cortisone in the kidney
- Blocks 11-B-dehd
Describe the mechanism of action of glucocorticoids
- Bind to intracellular receptors and migrate to the nucleus
- Dimerize and regulate gene transcription
- Rapid non-genomic effects of glucocorticoids and mediated through signalling systems in the cytosol
What are common glucocorticoid drugs?
- Hydrocortisone
- Prednisolone
- Dexamethasone
What regulates the metabolic effects of glucocorticoids?
• Enzymes e.g. cAMP dependent protein kinase (PKA)
•
What are the 4 ways glucorticoids can exert their effects?
- Transactivaiton: glucocorticoid binds to G response element and upregulates transcription
- Transrepression: transcription factors bind to negative G response element decreasing transcription
- Fos/Jun: glucocorticoids reduce the binding of fos/jun transcription factors to AP-1 regulatory site
- Nuclear factor: GR binds to transcription factor preventing transcription
What are the 4 physiological roles of glucocorticoids?
- Regulatory actions
- Metabolic actions
- Anti-inflammatory and immunosuppressive effects
- Actions on mediators of inflammatory and immune responses
What are the regulatory actions of glucocorticoids?
- Negative feedback: acts on hypothalamus and pituitary (CRF and ACTH) leading to reduced glucocorticoid release
- Cardiovascular: reduced vasodilation and fluid exudation
- Musculoskeletal: decreasing osteoblast and increasing osteoclast activity to give a tendency for osteoporosis
What are the metabolic actions of glucocorticoids?
- Decreased uptake and utilisation of glucose accompanied by increased gluconeogenis to cause hyperglycaemia and increased glycogen storage
- Increases catabolism and decreases anabolism, leading to muscle wasting
- Lipids: permissive effect on lipolytic hormones and a redistribution of fat as observed in cushings syndrome
What are the anti-inflammatory and immunosuppressive effects of glucocorticoids?
- Anti inflammation: decreased influx and activity or leukocytes
- Chronic inflammation: decreased activity of mononuclear cells, decreased angiogenesis and fibrosis
- Lymphoid tissue: decreased clonal expansion of T and B cells and decreased activation of cytokine secreting T cells
- Switch from Th-1 to Th-2 responses (dampening down cell mediated and acquired response)
What are the actions of glucocorticoids on mediators of inflammatory and immune responses
- Decreased production and action of cytokines including interleukins, TNF-a, cell adhesion factors and induced nitric oxide
- Reduced generation of eicosanoids due to decreased COX-2 expression
- Reduced generation of IgG and complement components in the blood
- Increased release of anti-inflammatory factors
- Overall reduction in the activity of the innate and acquired immune system
What is the main clinical use of mineralocorticoids?
Replacement therapy in Addisons
Describe the mechanism of action of fludrocortisone
- Increases Na+ reabsorption in the distal tubules
- Increases K+ and H+ efflux
- Acts on the intracellular receptors that modulate DNA transcription
Spironolactone
- Competitive antagonist
- Potassium sparing diuretic
- Used to treat hyperaldosteronsim, resistant hypertension, heart failure and oedema
Why is aldosterone not appropriate as a therapeutic agent?
The liver converts >75% of oral aldosterone to an inactive metabolite
What are the causes of Addison’s disease?
- 7/10 due to autoimmune disease e.g. adrenalitis
- TB
- Metastatic cancers
- Atrophy due to prolonged steroid therapy
- haemochromatosis
- Amyloidosis
What are the symptoms of Addisons disease?
- Anorexia
- Nausea and vomiting
- WEakness
- Hypotension
- Skin pigmentation
- Low sodium/ high potassium
- Chronic dehydration
- Sexual dysfunciton
Describe the treatment of Addisons disease
- Corticosteroid replacement therapy for life
- hydrocortisone main
- Prednisolone or dexamethasone
- If greater mineralocorticoid effects are needed, aldosterone is replaced with fludrocortisone
What is the main cause of hyperaldosteronism?
• Adrenal adenoma - Conn’s syndrome
How is Conn’s syndrome/adrenal adenoma treated?
- Surgical adrenalectomy
* Before surgery: use of a aldosterone antagonist e.g. spironolactone
Congenital adrenal hyperplasia
• C-21 hydroxyls enzyme is missing
- non hydroxylated versions of cortisol, corticosterone and aldosterone are made
- these lack normal activity and don’t negatively feedback on the HPA
• Treat with cortisol to replace the missing cortisol and cause negative feedback
• Replace the mineralocorticoid
What are the side effects of glucocorticoids?
- Suppression of response to infection and injury
- Opportunistic infections can be problematic
- Oral fungal and yeast infections can occur
- Impaired would healing
- Osteoporosis
- Hazard of fractures
- Hyperglycaemia
- Muscle wasting and weakness
- Inhibition of growth in children
- CNS effects
- Glaucoma
What is Cushing’s syndrome characterised by?
- Moon face and red cheeks
- Buffalo hump
- Thinning of skin
- Increased abdominal fat
- Easily bruising
- Poor wound healing
- Mood swings
