Cook - Gluco/Mineralocorticoids Flashcards
1
Q
What is the feedback mech for ACTH release?
A
- Cortisol is the main hormone that regulates feedback from the adrenal (at the level of ACTH and CRH)
- ACTH negative feedback on CRH
- Also circardian regulation and STRESS
2
Q
Cosyntropin
A
- Synthetic ACTH to test for cortisol production
- Major use in testing the integrity of the HPA axis to identify pts needing supplemental steroids
1. Measure cortisol, inject drug IM or IV, measure cortisol again in 30-60 min - Cosyntropin preferred bc animal product may contain high levels of vasopressin
3
Q
What mediators induce/INH HPA axis release of cortisol?
A
- IL-1, 2, 6, and TNF-alpha: induce ant pit release of ACTH and hypothalamic release of CRH
- Cortisol feeds back to hypothal and pit to regulate response to inflammatory mediators -> also has direct effect on the immune system, DEC inflam and inflam cells
- Major stressors, esp. SURGERY, can overcome cortisol feedback INH, causing INC cortisol release
4
Q
What are the 2 classes of adrenocortical steroids? How are they related?
A
- Mineralocorticoids and glucocorticoids (21 carbons; androgens have 19)
- Very little difference in these structures: even for androgens and estrogens, there is some cross-binding
- All work on nuclear receptors, and production of new proteins
5
Q
How are adrenocortical steroids synthesized (basics)?
A
- ACTH stimulates synthesis of all these hormones from cholesterol
- So many CYP450 enzymes in this process, and some drugs INH all of this by INH it right at the beginning
- REMEMBER: steroid hormones work via nuclear receptors (any hormones that come from cholesterol, incl Vit D)
6
Q
What is the difference b/t physiologic and pharmacologic doses of GCS? Why is it important?
A
- Difference is the DOSE
1. Insulin example: even the insulin pump is not able to regulate levels very tightly - This has an impact on feedback regulation: much more influence, and much longer lasting
1. GCS example: may need to provide cortisol to folks who have been on GSC long-term who are going to have surgery -> DEC capacity to resist stress
7
Q
Why is the MOA of GCS relevant to their onset/duration?
A
- Most effects occur through binding to nuclear receptors, and either INC or DEC DNA transcription, leading to changes in concentration of specific proteins
- Most effects are DELAYED by several hours, and last longer
8
Q
Do adrenocortical steroids have limited or broad effect?
A
- Very BROAD effect
- Regulation of carb, protein, and lipid metabolism (cortisol)
- Maintain fluid and electrolyte balance (aldosterone)
- Capacity to resist stress
9
Q
How do GCS affect protein and carb metabolism?
A
- GCS (cortisol) protect brain during starvation (even overnight fast) by keeping glucose elevated
- MOA: INC gluconeo and glycogenolysis in liver
1. Peripheral tissues:
a. DEC glucose utilization
b. INC proteolysis (AA for gluconeo)
c. Activate lipolysis (glycerol for gluconeo and FA for energy needed for glu syn) - All of these effects OPPOSE INSULIN
1. Can create major problems in diabetic pts: any pt w/high fasting glu can be “pushed” from pre-diabetes to diabetes
10
Q
What are some of the therapeutic and AEs of GCS (image)?
A
- RA: anti-inflam, immunosuppression
- Prednisone, stronger GCS, cause euphoria
-
AEs: don’t see the effects of infections
1. Block HPA axis -> psychiatric symptoms
2. Can get perforated gastric ulcers w/NSAIDs and huge infections, but not know it because no pain (can be a very DRASTIC problem)
3. Hirsutism - Most of the time, there is an understanding of how to control the problems
11
Q
What are the symptoms of Cushing Syndrome/Disease (image)?
A
- Buffalo hump: from maintenance of brown adipose tissue
- Lots of loss of muscle, so thin arms and legs
12
Q
How do the steroids compare to e/o in terms of anti-inflam and salt-retaining effects? What is unique about Dexamethasone?
A
- See attached table
- Dexamethasone does not interfere with cortisol measurement, and is able to suppress the HPA axis
1. NO salt retaining activity, and strong (note the equivalent dose column) - REMEMBER: Hydrocortisone is exactly the same compound as cortisol
1. Stress response in cortisol is very important post-surgically (and can last several days)
2. Suppression recovery may take up to 12 months
13
Q
How do cortisol levels change after surgery?
A
- Woman after breast surgery → important stress response (still elevated, even after 4 days)
- REMEMBER: cortisol response limited in folks on long-term steroid therapy
14
Q
Why is perioperative steroid therapy concerning?
A
- Long-term steroid use can suppress the HPA axis, leading to impaired ability of the body to respond to the stress of surgery
- Can also lead to:
1. Impaired wound healing
2. INC fragility of skin, superficial blood vessels, and other tissues -> mild pressure may cause hematoma or skin ulceration, removing adhesive tape may tear skin, and sutures may tear gut wall
3. INC risk of fracture, infections, GI hemorrhage, or ulcer - Supraphysiologic admin of GCS in immediate perioperative procedures produces: 1) HTN, 2) fluid retention, 3) hyperglycemia, 4) INC risk of infection
15
Q
If pt is on low-dose, short-term GCS, how should you tx them peri-operatively?
A
- Maintain normal daily dose of GCS (HPA axis suppression NOT needed)
- Monitor for hemodynamic instability peri-operatively
- Dosing:
1. Prednisone: <=5mg/morning
2. Methylprednisone: <=4mg/morning
3. Dexamethasone: <=0.5mg/morning
4. Hydrocortisone: <=20mg/morning
16
Q
If pt is on higer-dose, long-term GCS or has Cushing appearance, how should you tx them peri-operatively?
A
- Take usual morning steroid dose, then:
1. 50mg Hydrocortisone IV pre-sx, then 25mg q8h x 3 if lower extremity vascularization or total joint replacement
2. 100mg Hydro IV pre-sx, then 50mg q8h x 3, then taper to normal dose if open heart surgery, esophagogastrectomy, or total proctocolectomy - Any pt w/physical appearance of Cushing’s syndrome or w/following doses for >3 wks duration
1. Prednisone: >20mg/morning
2. Methylprednisone: >16mg/morning
3. Dexamethasone: >2mg/morning
4. Hydrocortisone: >80mg/morning - Will have more problems with these people
- Note: the doses here are 4x dose on other card
17
Q
If someone was taking high-dose steroids, but stopped 6 months ago, would they be ok for surgery?
A
- Depends on the pt
- Suppression recovery varies by pt, and some may take up to 12 months to recover
18
Q
How should steroid therapy be stopped? What are some things that can INH this?
A
- Tapered off to avoid acute adrenal insufficiency
- No compelling evidence favors any particular regimen of GCS tapering
- Short-term (up to 3 wks) of tx unlikely to produce HPA suppression
- Psychological dependence, re-emergence of original disease, and apparent HPA dysfunction can hamper tapering
19
Q
How can you evaluate HPA axis suppression?
A
-
Stop GC for 24 hrs; AM serum cortisol (before 8)
1. <5mcg/dL (138 nmol/L) = impaired axis
2. >10 (275) = normal -> continue on current GCS replacement dose on the day of surgery
3. 5-10: ACTH (corticotropin) stimulation test or empiric perioperative GCS therapy -
ACTH stimulation test: msmt of serum cortisol 30 min after 250 mcg ACTH stimulation
1. >18 (497) predicts adequate adrenal reserve during sx w/no need for GCS coverage perioperatively
20
Q
What are the symptoms of Addison’s disease? Adrenal crisis (image)?
A
21
Q
How should you treat Addison’s disease (3)?
A
- Life-threatening emergency -> TREAT (don’t wait for tests)
- ACUTE CRISIS: Dexamethasone IV q12h b/c it doesn’t interfere w/cortisol assay
- SUB-ACUTE: ACTH stimulation test for adrenal insufficiency, taper GC dose, and begin Fludrocortisone (MC) tx
- CHRONIC: Hydrocortisone (lowest dose to suppress symptoms)
1. Twice daily regimen: 2/3 in AM, 1/3 afternoon OR 10/5/2.5mg early AM/early PM/early evening
22
Q
What are the therapeutic uses for the GCS?
A
- Dexamethasone labeled for use in 85 diseases
- As a rule, GCS can be used interchangeably
- Often going to be thinking about long-term tx, so you will have time to adjust dose and check symptoms
23
Q
Why can’t you remove GCS immediately?
A
- If you remove drug immediately, you could have fatal consequences
- Cortisol stimulating gluconeogenesis, and without this stimulus, they will not have enough glucose to keep their brain operating
24
Q
How do corticosteroids affect skeletal muscle?
A
- Normal levels required for normal muscle function
1. Adrenocortical INSUFFICIENCY (Addison’s) causes diminished work capacity and fatigue due to DEC capacity of the circulatory system - An EXCESS of gluco- or mineralocorticoids will impair muscle function
1. 1o aldosteronism causes muscle weakness due to hypokalemia - Glucocorticoid TX can cause muscle weakness due to muscle wasting -> steroid myopathy via INC proteolysis
1. Using protein to convert AAs to glucose leads to muscle weakness, and some loss of K
25
Q
What are the effects of corticosteroids on the CNS?
A
- Direct effects on mood, behavior, and brain excitability
- GCS tx: results in EUPHORIA and feeling of well-being, high motor activity, insomnia, restlessness
- Addison’s: apathy, depression, irritability; some are psychotic
- Cushing’s: high incidence of neuroses and psychoses
26
Q
Basics of corticosteroid tx and dosing
A
- Risk/benefits of tx must be assessed in each pt
- Appropriate dose determined by trial and error
- Single dose usually not harmful
- Tx for 1 wk unlikely to suppress HPA axis
1. Longer-term tx imposes greater risk -> cessation after long-term tx has very serious consequences, and can even be FATAL
a. DEC ACTH release and atrophy of adrenal cortex -> if abruptly stop, can cause acute hypotension and/or hypoglycemia
2. Tapering methods different for e/patient
27
Q
Txs for RA, renal disease, DSEK, and allergic disease?
A
-
RA: oral prednisone
1. Pro-drug of prednisolone (active component) - Renal disease: oral prednisone
- Endothelial cornea transplants (DSEK): only use of prednisolone -> eye drops used for life, and immediately active, to prevent rejectiojn
-
Allergic disease: long-term tx (except anaphylaxis, which requires immediate epinephrine)
1. Anti-histamines for moderate symptoms
2. IV methylprednisolone for severe sxs
3. Intranasal steroids for allergic rhinitis (Flonase/Fluticasone now available generic, and formulation is causing some rxns)
28
Q
Why can drug formulation be a problem?
A
- Some skin creams can cause inflammation due to the compounds the steroid they are suspended in
1. Fluticasone/Flonase example
29
Q
Txs for ocular, skin, GI, and hepatic diseases, and lymphoma?
A
- Ocular diseases (iritis): Dexamethasone
- Skin diseases: Hydrocortisone
- GI diseases, e.g., chronic ulcerative colitis, Chron’s disease: Hydrocortisone, Prednisone, mostly replaced by newer NSAIDs
- Hepatic diseases: controversial -> Prednisone, Prednisolone
- ALL and lymphoma: anti-lymphocytic effect (several GCS)
30
Q
Mifepristone
A
- Used in high doses to tx Cushing’s (not used very often)
- Binds w/high affinity to GC receptor, making functionally inactive GC-receptor complex in nucleus -> ANTAGONIST of GC receptor
- ONLY for inoperable pts w/ectopic ACTH secretion or adrenal carcinoma who have failed to respond to tx manipulations
- Also an abortion pill (progesterone antagonist)
31
Q
Appreciate this.
A
Good job!
32
Q
What are the physiological actions of aldosterone? Deficiency?
A
- Acts on distal convoluted tubules in kidney:
1. Promotes Na+ reabsorption (always associated with water)
2. INC excretion of K+ and H+ - Overall effect is INC ECF, hypokalemia, and alkalosis
- Deficiency leads to Na loss, DEC ECF, hyponatremia, hyperkalemia, and acidosis
33
Q
What happens in aldosterone OD?
A
- Hypernatremia
- Hypokalemia
- Metabolic alkalosis
- EDEMA
34
Q
Fludrocortisone
A
- Addison’s
- Adrenocortical insufficiency
- Adrenogenital syndrome (CAH)
- Mimics actions of aldosterone -> renal (DCT) Na+ resorption and K+ excretion
- AEs: fluid imbalance, electrolyte imbalance (esp. hypokalemia), edema, CHF, cardiomegaly, and HTN
35
Q
What are the mineralocorticoid antagonists? MOA? AEs?
A
- Spironolactone
- Eplerenone: lower affinity, but less cross-rxn with androgen, progesterone, and corticosteroid receptors
- MOA: competitive binding of mineralocorticoid receptor in distal convoluted renal tubule
-
AEs: fluid or electrolyte imbalance, e.g., hypomagnesemia, hyponatremia, hypochloremic alkalosis, and hyperkalemia
1. Transient elevation of BUN
2. Gynecomastia, feminization, infertility,
3. Somnolence, dizziness, GI distress, urinary frequency
4. SJS/TEN
36
Q
GC/MC CV effects
A
- MC: INC Na+ retention, leading to HTN
1. Can lead to cerebral hemorrhage, stroke, and hypertensive cardiomyopathy - GC: enhance vascular reactivity to other substances, usually through INC synthesis of adrenergic receptors
