Adrenocorticosteroids and Adrenocortical Antagonists Flashcards
What are the three andrenocorticosteroids?
- Mineralocorticoids
- Glucocorticoids
- Androgens
With regards to the morphology of the adrenal gland what are the parts and what are they responsible for?
- Z.glomerulosa is controlled by angiotensin II and K+ to produce aldosterone
- Z.fasciculata is responsible for production of cortisol
- Z.reticularis is responsible for production of DHEA and estrogen
Discuss the Hypothalamus Pituitary Adrenal Axes with respect to cortisol (hydrocortisone) regulation and aldosterone regulation
Mineralocorticoids: Aldosterone - what is it? what regulates its synthesis? What are the effects of this?
Mineralocorticoids: Aldosterone
- Aldosterone = steroid hormone from cholesterol
Three systems regulate aldosterone synthesis:
- The renin-angiotensin system (main one)
- Blood potassium levels
- ACTH
- The renin-angiotensin system regulates extracellular fluid (ECF) volume
- ↓ ECF volume = ↓ perfusion pressure at the afferent arteriole of the renal glomerulus (baroreceptor)
- This stimulates the juxtaglomerular cells to secrete renin, a protease that cleaves angiotensinogen → angiotensin I → angiotensin II
- Angiotensin II has direct arteriolar pressure effects, and it stimulates aldosterone synthesis by binding to a G protein-coupled receptor in the zona glomerulusa
Mineralocorticoids and the renin angiotensin system - role of angiotensin I/II, aldosterone and its effect on renal sodium and blood volume (flow chart style)
What are the parts of the renal juxtaglomerular apparatus?
How is cholesterol converted to Pregnenolone (P5)?
- Cholesterol is the precursor of cortisol and aldosterone and converts to P5 via cytochrome P450 which is found in the liver and is the dependent enzyme
- Biotransformation of P5 to glucocorticoids:
- P5 → deoxycortisol → cortisol - Biotransformation of P5 to androgens
- P5 → DHEA → androstenedione - Biotransformation of P5 to aldosterone
- P5 → DOC → aldosterone
Describe Adrenocorticosteroid Transport
Cortisol
- 5% free
- 75% transcortin (CBG)
- 20% albumin
Aldosterone
- Almost no binding
Describe the steroid hormone action of cortisol (hydrocortisone)?
- Numerous effects; direct and permissive
- CHO, protein and lipid metabolism
- Increase blood-glucose overall; protects heart/brain
- Liver – gluconeogenesis, glycogen storage
- Periphery-decrease glucose use, increase protein and lipid breakdown - Anti-inflammatory and immunomodulatory effects
- Inhibit production of proinflammatory mediators - Stress coping support
- CNS; sense of well-being, mood and behaviour
- Cardiovascular integrity
- Stimulation for development of fetal lung-surfactant
Describe the steroid hormone action of aldosterone
- Fluid and electrolyte balance; Na+ and K+ homeostasis
- Rapid activation of Na+ channels in the apical membrane of principal cells (Distal Collecting Tubes + Collecting ducts)
- Promotes Na+ reabsorption, H+/K+ excretion
- Cardiovascular support; blood pressure
Modification of Glomerular Filtrate with reabsorption of sodium in the distal tubule and collecting duct
Distal tubule
* Reabsorption of 7% of Na+
* Impermeable to water → further decreases in concentration to a value lower than plasma
Collecting duct
* Reabsorption of 2-3% of Na+; permeability to water and of concentrated vs. dilute urine dependent on presence of vasopressin (ADH)
The steroid hormone preparations for the short-medium acting (<24hr) agents and its activity (potency)
- Cortisol - use as standard → 1 is “base” value
- Prednisolone and methylprednisolone are better anti-inflammatory vs. salt retaining
The steroid hormone preparations for the intermediate acting (24-48hr) agents and its activity (potency)
The steroid hormone preparations for the long acting (>48hr) agents and its activity (potency)
- Long-acting is 30x greater than cortisol
The steroid hormone preparations for the mineralocorticoid agents and its activity (potency)
Fludrocortisone and desoxycorticosterone acetate are better as salt retaining drugs than anti-inflammatory
What is the Special Case with steroid hormone preparations?
- Special case: topically active glucocorticoid – good anti-inflammatory
- Fluticasone Propionate (flonase)
- Very good option instead of antibiotics → avoid problem of antibiotic resistance
- Used for sinus infection, asthma, allergies - Glucocorticoid and progesterone antagonist:
-Mifepristone (treats “Cushing’s syndrome”)
Clinical applications - Hyperadrencorticism (Cushing’s syndrome) what is it? Its causes? its diagnosis?
- Marked by presence of elevated cortisol levels in the body – clinical signs of hypercortisolism
- Upper body obesity “moon face”, “buffalo hump”
- Thinning of skin; easily bruised
- Muscle wasting (thinning) of arms and legs (↓ muscle mass)
- Weakening of bones; osteopenia
- Elevated liver enzymes - Causes:
- Pituitary adenoma; women > men by 5X
- Iatrogenic; long term steroid treatment for another problem
- Ectopic ACTH syndrome
- Adrenal gland tumors - Diagnosis: clinical signs, blood tests, imaging
- 24-hour urine collection; elevated cortisol
- Provocative tests to rule out adrenal vs pituitary vs ectopic
What are the therapy options for Cushing’s?
- Surgery – Resectable tumors; pituitary, adrenal, ectopic
- Radiation – Alone or follow-up surgery of tumor
- Adrenocorticosteroid Inhibitors – Mitotane
- Adrenolytic; specific for adrenals - Hormone Synthesis Inhibitors
- Ketoconazole; most effective inhibitor; liver damage
- Aminoglutethimide; inhibits conversion of cholesterol to pregnenolone; adrenal tumors
- Trilostane; inhibits conversion of pregnenolone to progesterone (next step in synthesis) – available in the UK - Glucocorticoid receptor antagonists
- Mifepristone: at higher doses may be effective
- Used on inoperable patients (no other therapeutic option available) with ectopic or adrenal tumors not responding to other therapy
Clinical Applications - Hypoadrenocorticism (Addison’s disease) what is it? its causes? and discuss its acute vs chronic effects
Adrenal Insufficiency “Addison’s disease”
- Not enough production of cortisol (opposite of Cushing’s syndrome)
- Most commonly primary adrenal insufficiency from autoimmune disease and adrenal destruction (used to be common in cases of tuberculosis)
- Other common cause is abrupt steroid withdrawal
- Possible following surgery (no longer have stimulus to produce cortisol) for adrenal tumors or pituitary tumors
- Acute vs Chronic adrenal insufficiency
- Acute adrenal crisis is often due to abrupt withdrawal of long-standing glucocorticoid therapy, but can also precipitate from exacerbation of chronic adrenal insufficiency
- Acute emergency often; IV fluid support (isotonic NaCl) and IV corticosteroids (hydrocortisone), other supportive care as needed e.g. antibiotics (for possible bacterial infection)
- Chronic-similar signs to acute but less severe (not as intense but long term)
- Long-term glucocorticoid (hydrocortisone or prednisone) replacement therapy
- Fludrocortisone (mineralocorticoid) if primary Addison’s disease present
Clinical Applications – Non endocrine diseases
Non-endocrine Use of Glucocorticoids
- Anti-inflammatory and anti-allergy therapy
- Mainstay of glucocorticoid use/misuse in medicine
- Plethora of allergic conditions; most organ systems
- Reduce proinflammatory mediators by multiple mechanisms
- Intensive short-term or emergency therapy
- Anaphylaxis, shock, heat stroke
- Rapidly acting IV preparations of glucocorticoids
- Usually given in high doses for pronounced effects
- Immunosuppressive therapy
- Used to quiet an overzealous immune system that is detrimental – organ transplants (help body not reject new organ), autoimmune ds
- Neoplasia
- Glucocorticoids have antilymphoproliferative effects
- Useful for certain hematologic malignancies such as lymphoma, certain leukemias
- Adjunct therapy for inflammation following radiation and with mast cell tumors
Clinical Applications - Appropriate Glucocorticoid Therapy
- Glucocorticoids use in non-endocrine disease merely mask symptoms of condition being treated; need to correct underlying problem
- Adverse effects of steroid therapy can be minimized
- Lowest dose possible
- Low potency steroids; prednisone
- Alternate day therapy; give HPA a day off
- Tapered reduction of steroid therapy to allow HPA axis time to recover following treatment
Clinical Applications - Mineralocorticoid Antagonists
- Primary aldosteronism (want to ↓ levels of aldosterone); adrenal adenoma is usual cause
- Signs of hypertension and hypokalemia
- Treatment is usually surgical; can be curative
- Blockade of aldosterone can be accomplished also with drugs
-Spironolactone, Eplerenone - Hypertension and heart failure; increased aldosterone contributes to adverse effects
- Eplerenone
Adrenal: Take Home Messages
- Adrenal steroids are very powerful, affecting the entire body
- Aldosterone (Z. Glomerulosa)
- Cortisol and androgens (Z fasciculata and Z reticularis) - Aldosterone (mineralocorticoid) controlled by kidney renin-angiotensin system
- Cortisol (Glucocorticoid) by hypothalamic-pituitary ACTH
- Aldosterone controls kidney sodium and water retention
- Cortisol controls metabolism, promoting glucose regeneration and entry to the blood
- Cortisol, but not aldosterone, largely carried bound to proteins in the blood
- Pharmacological targets: enzymes involved in steroid synthesis, as well as steroid receptors
- Mineralocorticoid (MR) and glucocorticoid (GR) receptors are very similar, so high cortisol increases sodium retention
- Different synthetic corticosteroids available – MR as well as GR specific, differing in duration of action, some only surface active, as well as some antagonists (mifepristone, GR antagonist; spironolactone, MR antagonist)
- Widely used as anti-inflammatories, immune suppressants treatment of glucocorticoid insufficiency, treatment of women in premature labor
- Very powerful drugs, so long term glucocorticoids suppress ACTH, and must be tapered off slowly – or the patient may suffer an Addisonian crisis when the glucocorticoid is stopped
