What is the known ACTH analog?
Synthetic ACTH (AA 1-24) Cosyntropin (Cortrosyn)
What glucocorticoid analogs are on the market?
Cortisol=hydrocortisone (Cortef, Hydrocortone)
Prednisolone (Delta- Cortef)
Budesonide Inhalation (Pulmicort)
What are the mineralcorticoid analogs?
What are the mineralcorticoid antagonists?
Spironolactone and Eplernone
What are some inhibitors of adrenocortical steroid synthesis or action?
What is ACTH made from?
proopiomelanocortin (POMC) (which is cleaved to form ACTH, MSH and endorphins)
Briefly describe the ACTH axis
Circadian rhythm and stress (sometimes in the form of immune factors like IL-1/2/6, TNFa) signal release of CRH from the hypothalamus, which stimulates release of ACTH from the anterior pituitary, and subsequent adrenal cortex hormone production
NOTE: It makes sense that inflammatory factors like IL-1 would stimulate ACTH and CRH given that cortisol inhibits their production via binding to white cells
Which is released from the adrenal cortex in large quantites, cortisol or aldosterone?
Cortisol is released at 10 mg/day and aldosterone is produced at 0.125 mg/day (100x difference).
What enzyme deactivates cortisol in cells where aldosterone acts to cortisone (kidney, colon, and salivary glands)?
11B-HSD type II (thus cortisol cannot bind to aldosterone receptors!)
In addition to direct effects, glucocorticoids also have permissive effects. What does this mean?
ex. epi and nor have minor effects on lipolysis in the absence of glucocorticoids, but much greater in their presence (this ex. is due to increased synthesis of lipases) due to upregulation of adrenergic receptors by cortisol
Do corticosteroids act quickly?
Most of the effects of steroid hormones are via upregulation of DNA transcription so they are delayed several hours. However, a few effects are immediate and are mediated by membrane receptors
What are the effects of glucocorticoids on blood glucose?
They protect the brain during starvation by keeping blood glucose elevated via increased gluconeogenesis and glycogenolysis in the liver.
Also, in the periphery glucosteroids decrease glucose uptake, increase proteolysis (to provide AAs for gluconeogenesis) and lipolysis (gycerol for gluconeogenesis)
How do glucocorticoids affect lipids?
In addition to promoting lipolysis, cortisol promotes redistribution of body fat and
athey also have permissive effects on other agents such as GH and b-adrenergic receptor agonists (iso and nor) in increasing lipolysis in adipose tissue.
An excess of either glucocorticoids or mineralcorticoids will affect muscle how?
impair muscle function (primary aldosteronism causes muscle weakness via hypokalemia and glucocorticoids via increased proteolysis and Ca2+ loss)
How do glucocorticoids affect the brain?
It results in euphoria and feelings of well-being, high motor activity, insomnia, and restlessness
(in addison's disease, you might see apathy, depression, and irritability)
How do glucocorticoids affect the inflammatory process?
They are anti-inflammatory and inhibit:
-phospholipase A2 action via lipocortin
-production and release of cytokines (especially IL-1, IL-2, IL-6, and TNFa)
-histamine and serotonin release
What is the half-life of cortisol, hydrocortisone, or cortisone acetate?
short (all of these can be given PO, IM, or IV)
What is the half-life of prednisone, prednisolone, or methylprednisolone?
intermediate (note prednisone can only be given PO, prednisolone IM and IV, and methlprednisolone IM, IV, and PO)
What are the long acting glucocorticoids?
Dexamethasone (IM, PO, topical, IV) and triamcinolone (PO, topical)
What are the AEs of glucocorticoid therapy?
-suppression of ACTH and TSH production from the pituitary (recovery can take weeks to months)
-arousal and euphoria, followed by depression and insomnia commonly
Other uses of glucocorticoid therapy in men?
can suppress gonadotroph secretion causing hypogonadism due to suppressed testosterone production
Other glucocorticoid therapy in women?
can stop ovulation, or cause dysmenorrhea or dysfunctional uterine bleeding
Other glucocorticoid therapy in children?
stunted linear growth (decreased GH and inhibition of IGF-1)
How would acute adrenal insufficiency disorders of the adrenal gland or abrupt withdrawal of glucocorticoids be treated?
IV isotonic NaCl + 5% glucose + corticosteroids (after a dexamethasone test) or
IV hydrocortisone (cortisol)
How would chronic adrenal insufficiency disorders (e.g. Addison's) with less severe symptoms be treated?
daily hydrocortisone or cortisone acetate (2/3 dose in morning and 1/3 evening)
or dexamethasone or prednisone
-add additional mineralcorticoid therapy if needed –(fludrocortisone acetate)
What glucocorticoid has been used for rheumatic disorders?
PO prednisone usually (and renal diseases)
How would you treat allergic disease?
anaphylaxis requires immediate epi
antihistamines for moderate symptoms
IV methylprednisolone for sevre symptoms
Intranasal steroids for allergic rhinitis (fluticasone)
Other uses of glucocorticoids?
-ocular diseases (dexamethasone)
-skin diseases (hydrocortisone)
-GI disease (Chronic UC and CD)-hydrocortisone, prednisone, and budesonide (high first pass effect)
-hepatic disease (prednisone, prednisolone)
-lymphocytic leukemia and lymphoma
-asthma (budesonide inhalation suspension)
In general, the most used systemic steroids in practice are what?
hydrocortisone, methylprednisolone, and dexamethasone
What are the AEs of spironolactone?
anti-androgen effects (gynecomastia) and can cause decreased spermatogenesis
NOTE: Eplerenone is similar to spiro but is much more specific for the mineralcorticoid receptor and has little or no anti-androgen effect
AEs of aldosterone therapy (fludrocortisone)?
-excessive salt and water retention
-increased BP and CHF
How is ketoconazole used for tx in Cushing's syndrome?
inhibits P450scc (desmolase) to P45017a to block cortisol production (blocks all steroid hormone synthesis)
Other uses of keto?
adrenal carcinoma, breast and prostate cancer, and hirsutism
AEs of keto?
How can aminoglutethimide (Cytadren) used for treatment of Cushing's disease?
It inhibits P450scc (converts cholesterol to pregnenolone) and inhibits all steroid production
How can the AEs of steroid use be minimalized?
-local application (for example aerosols for asthma)
-alternative day therapy (to reduce pitutiary suppression)
-tapering the dose soona fter achieving a therapeutic response
What is Flucticazone (Flonac)?
a glucocorticoid that has recently gone generic (December 2015) and has since been associated with inflammatory rxns because its insoluble and a new emulsifying substance is being used which is causing the rxn
What things are released from POMC when it is broken down?
ACTH, a-MSH, y-MSH, CLIP, y-lipotrophin, B-endorphin
What is the major clinical use of ACTH?
is in testing the integrity of the HPA axis to identify patients needing supplemental steroids.
•Test of HPA axis: Measure cortisol, inject drug I.M. or I.V. measure cortisol at 30 to 60 min.) Use a synthetic ACTH called Cosyntropin
Effects of steroids
•Regulation in carbohydrate, protein and lipid metabolism
•Maintenance of fluid and electrolyte balance
•Preservation of normal function of cardiovascular system, immune system, kidney, skeletal muscle endocrine system and nervous system
•Capacity to resist stressful circumstances such as noxious stimuli and environmental changes
Effects of Aldosterone on CV system
•The most striking effects on the cardiovascular system are from mineralocorticoid actions to increase Na+ retention resulting in hypertension.
•These effects can lead to cerebral hemorrhage, stroke and hypertensive cardiomyopathy.
•Another major effect is to enhance vascular reactivity to other substances (usually through increased synthesis of adrenergic receptors).
How do glucocorticoids affect blood cells?
Glucocorticoids increase hemoglobin and erythrocytes.
•Addison’s disease increases lymphocytes. Glucocorticoid therapy decrease lymphocytes.
•Glucocorticoids also decrease eosinophils, monocytes and basophils (in a few hours after administration).
•Glucocorticoids increase polymorphonuclear leukocytes.
How are steroids typically given?
•Effective when given by mouth. Absorbed readily from intramuscular sites, conjunctival sac, skin, respiratory tract, and other local sites.
How does cortisol circulate?
•Circulating cortisol is 90% bound to proteins. Only unbound corticosteroids can enter cells.
What proteins are the main binders of cortisol in blood?
•Two proteins account for binding - corticosteroid binding protein (CBP, an a-globulin secreted by the liver) and albumin.
CBP has high affinity for binding, but low capacity, while Albumin has low affinity, but high capacity.
What situations might you see increased levels of CBP?
CBP increases several-fold in pregnancy and during estrogen treatment.
Which steroids have no mineralcorticoid activity?
The long-acting glucocrticoids, dexamethasone and betamethasone (these are also the most potent)
How would you treat Congenital adrenal hyperplasia (a genetic disorder lacking enzymes to produce cortisol or aldosterone or both-results in increased ACTH secretion for lack of feedback)
Hydrocortisone with or without fludrocortisone acetate