Adrenal Corticosteroids (Welch) Flashcards
Where are corticosteroids produced?
Adrenal Cortex
What are 3 classes of adrenocortical steroids?
- Glucocorticoids
- Mineralocorticoids
- Androgens
What are the adrenocortical steroids Glucocorticoids?
- Cortisol
2. Corticosterone
What are the adrenocortical steroids Mineralocorticoids?
Aldosterone
What are the adrenocortical steroids androgens?
Dehydroepiandrosterone
Are adrenocortical steroids synthesized and released by stimulation or are they stored, then released with stimulation?
Synthesized, not stored
What is the stimulus for Adrenocortical steroid synthesis and release?
fight or flight(severe infection, surgery, parturition, cold, exercise, stress)
Where do the stimuli for Adrenocortical steroid synthesis initially act?
hypothalamus to release CRH (corticotropic releasing hormone)
Where does Hypothalamic CRH act?
Anterior Pituitary to release ACTH (adrenocorticotropic hormone)
Where does Anterior Pituitary ACTH act?
Adrenal cortex
What inhibits the Hypothalamus from releasing CRH as well as the Anterior Pituitary from releasing ACTH?
Cortisol (glucocorticoid)
Synthesis and release of ACTH by anterior pituitary controlled by 3 main factors?
- Diurnal basal steroidogenesis
- Negative feedback from adrenal steroids (cortisol)
- Stress overrides inhibition of ACTH to increase release to aide fight or flight response
Is ACTH effective orally?
No must be administered IM or IV
Does straight ACTH have a long half-life?
No approximately 15 minutes
ACTH is a product of what?
Proopiomelanocortin (POMC)
What are 2 things that come from POMC?
- ACTH
2. B-endorphin
In fight-or-flight, what are the positive effects of the 2 POMC derivatives, ACTH and B-endorphin?
- ACTH will get Cortisol to feed body with sugar
2. B-Endorphin is endogenous opiod to decrease pain and keep body from going into shock during fight or flight
Coritcosterone, Cortisol, Testosterone, and Aldosterone all start from what first derivative of Cholesterol?
Pregnenolone
What is required for the conversion of cholesterol to Pregnenelone, the precursor to a bunch of adrenocoritical steroids?
ACTH and CRH to cause increase in cAMP leading to 20 alpha-hydroxylase to convert cholesterol to pregnenolone which is the rate-limiting step
Describe the cholesterol to aldosterone pathway.
CRH to ACTH to ↑cAMP to cholesterol + 20α- hydroxylase to Pregnenolone to Progesterone+21- hydroxylase to Corticosterone to 10-OH- Corticosterone to Aldosterone
Describe the Cholesterol to Cortisol pathway
CRH to ACTh to increased cAMP to cholesterol + 20 alpha-hydroxylase to pregnenolone to 17-OH pregnenolone to 17 OH_progesterone to 11-desoxycortisol to cortisol
The synthesis of cortisol does what to the release of CRH and ACTH?
Inhibits the release of CRH and ACTH
What are 2 functions of ACTH?
- Stimulates 20α-hydroxylase rate limiting step of conversion of cholesterol to pregnenolone
- Maintain the integrity of adrenal cortex
The synthetic peptide for ACTH, Cosyntropin (Cortrosyn) is used how?
Diagnostically, if given, cortisol levels should rise within 30 minutes
What is an inhibitor of 20-hydroxylase which will inhibit cholesterol to pregnenolone conversion, thereby inhibiting the production of Cortisol, Corticosterone, Aldosterone and Dehydroepiandrosterone?
Aminoglutethimide
What pt would indicate Aminogluthethemide treatment and what would be the side effects to that treatment?
- Cushing’s syndrome
- Profound Adrenal tumors
- Pt will have mineral imbalances, water retention preoblem, infertility
What are 2 things that Aminoglutethimide inhibits?
- 20 alpha-hydroxylase secretion
2. Aromatase that converts androgens to estrogens
What are 2 clinical uses for Aminoglutethimide?
- Hypersecretion of cortisol from adrenal tumors
2. Possible treatment for breast cancer
What are 3 adverse effects of Aminoglutethimide treatment?
- Hirsutism
- Hypothyroidism
- Leucopenia
What is a more directed chemotherapy to block cortisol, corticosterone, and aldosterone synthesis by blocking the 11 beta-hydroxylase from converting 11-deoxycortisol to cortisol?
Metyrapone
What steroid synthesis does Metyrapone NOT inhibit?
Dehydroepiandrosterone
What are 3 uses of Metyrapone?
- Diagnostic for PH / PIT / AC problems
- Treat adrenal neoplasms not under control of ACTH
- Treat Cushing’s syndrome
How is Metyrapone used diagnostically?
If you have confirmed that the adrenal cortex is normal w/ACTH, then metyrapone will cause 11-desoxycortisol to increase and a decrease in cortisol
If give Metyrapone diagnostically and 11- desoxycortisol excretion does not increase as desired, where does the problem lie?
In hypothalamus or anterior pituitary
What is a non-FDA approved treatment that is cytotoxic for adrenals and can attenuate Cushing’s disease that results from over-secretion of cortisol by a tumor or ectopic production of ACTH?
Mitotane (Lysodern) derivative of DDT
When a patient has inoperable adrenal tumor, they can be given the DDT derivative Mitotane, but what will be the follow on treatment?
Patient will be on steroid supplementation for life
What is an antifungal that inhibits glucocorticoid synthesis at higher doses, can be used to treat Cushing’s syndrome?
Ketoconazole
In general, what do steroids do when they act on the cell?
Cause release of HSP-90(heat shock protein-90), which keeps DNA folded, to open the DNA up allowing for DNA to be transcribed to mRNA and then translated to protein
What are 8 general effects of natural hormones?
- Carb and protein metabolism
- Electrolyte and water balance
- Lipid metabolism
- Cardiovascular
- Skeletal m.
- Growth and Cell division
- CNS
- Anti-inflammatory and immunosuppressive
Cortisol has a huge effect on what?
Carb and protein metabolism. Will increase glucose uptake in to eyes, brain, and large muscles (those things for fight or flight) and decrease glucose utilization in other cells
Adrenal insufficiency disease that has symptoms of decreased blood glucose (hypoglycemic), decreased mobilization of protein and fat, muscle weakness, and increased susceptibility to stress and infection?
Addison’s disease
What is an adrenal excess disease that has symptoms of increased blood glucose (hyperglycemic), diabetes mellitus, decreased tissue protein, increased plasma volume, and masculinization?
Cushing’s syndrome
What is the only difference between diabetes mellitus and Cushing’s syndrome?
Adrenal tumor in Cushing’s
Would an addison’s disease patient be alright taking insulin?
No. Will be hypersensitive because they are always hypoglycemic
What adrenocorticoid steroids are addison’s disease patients missing?
- Glucocorticoids (cortisol)
2. Mineralocorticoids (aldosterone)
Moon face, thin skin, obese with thin legs, poor wound healing, are all characteristics of what?
Cushing’s syndrome
What is decreased in Cushing’s syndrome?
- Glucose uptake by cells
- Glucose utilization by cells
- Protein synthesis by cells
What is increased in Cushing’s syndrome?
- Plasma glucose
- Urinary glucose
- Gluconeogenesis from proteins in cells
What adrenocorticosteroid is the major controller of Na retention?
Aldosterone
In Cushing’s disease, what does the increase in Aldosterone lead to?
More sodium retention so plasma has more volume causing edema and moonface
Because sodium is retained in the kidneys, what is excreted?
Hydrogen and potassium
What is caused by the excess loss of hydrogen and potassium in a Cushing’s syndrome patient who is retaining Na due to increased Aldosterone?
- Alkalotic
2. Hypokalemic
Hypokalemia leads to what symptoms?
- Cardiac arrhythmias
2. Muscle weakness
Will an Addison’s disease patient have high or low plasma volume?
Low plasma volume
What wil be the symptom of an Addison’s disease patient retaining Hydrogen?
They will be acidotic and will hyperventilate
What will be a symptom of an Addison’s disease patient retaining postassium?
Hyperkalemia will cause cardiac problems
Cortisol and corticosterone, when hypersecreted will redistribute body fat where?
Neck and face (away from extremities)
Is aldosterone effective in lipid metabolism?
No
The weakness and fatigue in Addison’s is due to what?
Reduced circulation (decreased plasma volume)
Muscle weakness in Cushing’s syndrome is due to what?
Hypokalemia
Muscle loss in Cushing’s sndrome is due to what?
Increased gluconeogenesis
What 2 things glucocorticoids can inhibit with respect to the cell?
- Cell Division
2. DNA Synthesis
How do steroids reduce manifestations of inflammation?
- Reduced number of peripheral leukocytes
- Interfere with leukocytes and macrophages
- Inhibit phospholipase A2
What are 2 major players of inflammation that steroids inhibit to exert their ant-inflammatory effect?
- Phospholipase A2 to decrease production of prostaglandins in the body and leukotrienes in the lungs
- Inhibit NF-κβ to decrease the stimulation of pro- inflammatory proteins
What patient would be more prone to apathy and depression: Addison’s, Cushing / Steroid patient?
Addison’s disease
Which patient would have mood elevation, insomnia, and restlessness: Addison’s, Cushing / Steroid patient?
Cushing’s / Steroid patient
Do steroids treat the underlying cause of inflammation?
No, strictly palliative to inhibit the early and late phenomena of inflammation
Virtually every cytokine is stimulated by what and is therefore inhibited by high-dose steroids?
NF-kB
What do glucocorticoids directly inhibit which inhibits the production of NF-kB that stops all the inflammatory protein signaling?
lkB-kinase
Most adverse effects of steroid administration occur when?
Chronic administration
What is the recovery for the pituitary and adrenals after long-term steroid treatment?
9 months
What steroids do not contribute to hypokalemic alkalosis and edema?
- Triamcinolone
2. Dexamethasone
What class of adrenocortical steroids alter mucosal defense mechanisms and contribute to ulcers. Can be found in Rheumatoid arthritis patients?
Glucocorticoids
What is a risk with long-term steroid use that can be treated with bisphosphonates?
Osteoporosis
What is a steroid therapy giving a single dose of intermediate acting Glucocorticoid on alternate mornings at 8am in an amount equivalent to the total dose ordinarily given over 48hrs to mimic the natural circadian rhythm of cortisol?
Alternate day therapy
Why does the alternate day therapy give the glucocorticoid dose at 8 am?
Cortisol peaks at 8 am when hypothalamic- pituitary axis is lowest
Why give an intermediate acting glucocorticoid for the alternate day therapy?
The shorter half life allows hypothalamic-pituitary axis to undergo its circadian rhythm but still have pharmacodynamic effect up to 36hrs
What is the goal of alternate day therapy?
- Minimize metabolic effects and keep anti-inflammatory effects
- Stimulate normal cyclic steroid levels
Can alternate day therapy be used to treat people with autoimmune disease like Rheumatoid Arthritis?
No
Will a patient on alternate day therapy have a near-normal response to Metyrapone test (increase in 11-desoxycortisol excretion)?
Yes
What is another reason to use alternate-day therapy?
To slowly stop steroid therapy
Steroids used in acute cases after cessation of long-term steroid treatment, in chronic diseases where steroids are insufficient, or in hypopituitarism lacking ACTH, all have the goal of what?
Replacing needed steroids
What are 2 steroids used along with aspirin in the treatment of Rheumatoid Arthritis?
- Prednisone
2. Triamcinolone
When would the steroid Prednisone be indicated to treat Rheumatic Carditis?
For congestive heart failure, arrhythmias that do not respond to salicylates
Why are steroids not treatment of choice for allergic diseases?
Slow to act
What steroids are administered IV in life-threatening allergic situations?
- Dexamethasone
2. Methylprednisolone
What is the treatment for bronchial asthma when all other means have failed?
Glucocorticoid by conventional route (inhalation) then methylprednisolone IV followed by prednisolone oral
Can steroids be given daily for the prevention of bronchial asthma without the risk of adrenal suppression?
Yes, in low does (6-8 inhales 50μg/day) (Beclomethasone diprorionate, triamcinolone acetonide, flunisolide)
Should steroid eyedrops be prescribed if the eye is infected
No
What is the risk for treating eye inflammation with a steroid in a person with Glaucoma?
Risk of increasing intracellular pressure
What steroid is best for Lymphoma treatment in children?
Prednisone
Why is Prednisolone useful for treating breast cancer?
If decrease adrenal cortex, will decrease androgen production, which decreases estrogen
What is the dosage for steroid Prednisone treatment in organ tansplants and what is it doing?
mg dosing (vs μg for asthma treatment) delays cell-mediated immunity
Can Prednisone be used to treat ulcerative colitis or Crohn’s disease?
Yes, in mg doses
What is ideal for the pharmacodynamics of steroids?
Desire low sodium retention to decrease the edema and increased blood pressure from water retention while still having anti-inflammatory effects
What are 2 synthetic steroids that have good anti-inflammatory potency while having low sodium retention?
- Prednisolone
2. Traimcinolone
What is the character of glucocorticoids in the plasma?
Highly protein-bound so has many drug interactions
What is a huge drug interaction with steroids?
NSAIDS. Displace the glucocorticoid from the binding globulin and increase glucocorticoid effect on the body
Are steroids classified by their therapeutic use?
No
How are steroids classified?
By extent to which they suppress ACTH by negative feedback
How long is short-acting ACTH suppression?
24-36 hrs
How long is intermediate-acting ACTH suppression?
48 hrs
How long is long-acting ACTH suppression?
Greater than 48 hours
What are 4 oral short-acting steroids?
- Cortisol
- Cortisone
- Corticosterone
- Methylprednisolone
What are 2 intermediate-acting steroids?
- Prednisolone
2. Triamcinolone
What are 2 long-acting steroids?
- Dexamethasone
2. Betamethasone
As steroids are altered to try and increase their anti-inflammatory effect and decrease their Na retention, a substitution at which Carbon will lead to loss of the mineralocorticoid (aldosterone) activity?
C16
What is essential at C11 for a steroid to exert glucocorticoid action?
Hydroxyl or Ketone
Glucose metabolism and what other steroid characteristic are linked because the same receptor mediates both on the cell?
Anti-inflammatory action
What are 2 steroids that are prodrugs and what must they convert to in order to exert their action?
- Cortisone convert to active Cortisol
2. Prednisone convert to active Prednisolone
What is the drug of choice for systemic anti-inflammatory effects?
Prednisolone
Why is cortisone not used as a systemic anti-inflammatory?
Has higher mineralocorticoid action (Na retention)
How is Predisone converted to its active form Prednisolone?
Liver type I 11B-hydroxysteroid dehydrogenase
Can prednisone bind by itself to its receptor on the cell?
No. Must be converted to Prednisolone first.
What is relatively more toxic than other glucocorticoids?
Triamcinolone
Which has greater anti-inflammatory effect: Cortisone or Triamcinolone?
Triamcinolone
What is the character of the C1-C2 bond of short acting versus intermediate and long acting steroids?
Short acting have single bond at C1-C2 Intermediate and long acting have double bond at C1- C2
Of the short acting hydrocortisone (cortisol) and cortisone, the intermediate acting prednisone and prednisolone, and the long acting dexamethasone, which one has a methyl group on C16?
Dexamethasone
Of the short acting hydrocortisone (cortisol) and cortisone, the intermediate acting prednisone and prednisolone, and the long acting dexamethasone, which one has the lowest sodium retention and the most anti-inflammatory potency
Dexamethasone
Of the short acting hydrocortisone (cortisol) and cortisone, the intermediate acting prednisone and prednisolone, and the long acting dexamethasone, which one has the highest sodium retention and the most anti-inflammatory potency?
Hydrocortisone
If a person has an adrenal insufficiency (e.g. Addison’s disease) when should their appointment be scheduled?
Mornings when cortisol is higher
What should the dentist seek to alleviate and why on a patient with adrenal insufficiency?
Stress. It can increase cortisol demand.
If pt has adrenal insufficiency and the surgery scheduled is major, or will last more than an hour, or will involve general anesthesia, will their normal steroid dose be adequate?
No, they will require steroid supplementation
Will nitrous oxide or oral benzodiazepine sedation reduce plasma cortisol levels?
No
What sedative drug class will increase cortisol metabolism and reduce plasma levels of cortisol and are therefore contraindicated in a patient with adrenal insufficiency?
Barbiturates
If a patient is scheduled for surgery and they are taking an adrenocorticoal antagonist (aminoglutethimide, ketoconazole, Metyrapone,Trilostane, Mitotane) what should they be instructed to do with the consent of their prescribing physician?
Discontinue steroid antagonist 24 hrs prior to surgery
What local anesthetic is indicated at the end of long procedures for pain control of pt with adrenal insufficiency?
Long-acting bupivicaine
What are 2 things that can exacerbate hypotension and cause adrenal-insufficiency like symptoms?
- Blood/fluid loss
2. Anticoagulation therapy
Patients whose blood pressure is at or below what mmHg should receive 5% dextrose fluid replacement, a vasopressor, or a glucocorticoid?
100 / 60
What should a dentist be monitoring for to take quick corrective action on a patient with adrenal insufficiency?
Signs of hypotension, hypoglycemia, or hypovolemia
