3.3 Corticosteroids

Treatment of Cushing's Disease - If there is a well defined microadenoma, the preferable surgical procedure is a _______ - Alternatively, you can have 85-90% resection of the anterior pituitary Or - Pituitary radiation

*Cushing's Disease* 1. Transsphenoidal microadenectomy is preferable if a well defined microadenoma is identified

Aldosterone promotes the reabsorption of sodium. Where does this mostly take place? Where else in the body?

- ***Renal Tubules*** -Sweat & salivary glands -GI mucosa -Across cell membranes in general

*** - Primary Adrenal insufficiency is known as what? - What is the general pathophysiology? - Most commonly due to what?

- *Addison's Disease* (Gland itself) - Adrenal glands unable to produce sufficient quantities of glucocorticoid, mineralocorticoid, and androgen. -Most commonly due to bilateral adrenal destruction from *autoimmune disease*

Congenital Adrenal Hyperplasia (CAH): Another common defect is with what enzyme? In this form of CAH, a failure of cortisol synthesis results in: - Excessive ______ production - Hyperplasia of what gland? - Build up of precursors, most notably _______

- 11 beta hydroxylase -Excessive ACTH production -Adrenal gland hyperplasia - Build up of precursors, including deoxycorticosterone

Congenital Adrenal Hyperplasia (CAH): - Due to specific congenital defects in cortisol synthesis. - Most commonly due to which enzyme?

- 21β hydroxylase

Glucocorticoids: What long-acting glucocorticoid do we need to know? What is its (anti-inflammatory : salt-retaining) effect ratio?

- Dexamethasone - 30:0 (Pure anti-inflammatory effect)

Glucocorticoids: What are the 6 short-to-medium acting glucocorticoids?

- Hydrocortisone - Cortisone - Prednisone - Prednisolone - Methylprednisolone - Meprednisone

ADRENOCORTICAL ANTAGONISTS: Metyrapone - Selectively inhibits ______ hydroxylation, which results in increased 11-deoxycorticosterone. This produces: a ________ effect and diversion to _____ synthesis. - Use during pregnancy?

- Metyrapone Selectively inhibits 11 beta hydroxylation resulting in mineralocorticoid effect and diversion to androgen synthesis. - Can be used during pregnancy 2. Aminoglutethimide Blocks conversion of cholesterol to pregnenolone reducing synthesis of all hormonally active steroids. (Previously used to decrease estrogen production in breast Ca)

Aldosterone: - Promotes the reabsorption of what ion? -Is it protein bound? -T1/2? - Metabolized where?

- Salt - Not significantly protein bound - 15-20 minutes - Metabolized in liver, conjugated for renal excretion

***Long-term steroid users may exhibit symptoms of Adrenal Insufficiency associated with surgical stress. This is due to: - Prolonged suppression of ______ - Inadequate replacement of ______ - Abrupt _______ of steroids in the perioperative period.

- hypothalamic-pituitary-axis suppression - steroids - withdrawal

OTHER MINERALOCORTICOIDS: Deoxycorticosterone (DOC) It is a precursor of _________ It is under primary control of what hormone? What is its (anti-inflammatory : salt-retaining) effect ratio?

- precursor of aldosterone - *ACTH* as opposed to renin-angiotensin 0:20 (has NO anti-inflammatory effects)

Glucocorticoids: Cortisol -Other name? -Involved in what 4 things? - Production and release of cortisol is controlled by the CNS though sensitive negative feedback loops

-(Hydrocortisone) - Involved in: -Regulation of intermediary metabolism -Cardiovascular function -Growth -Immune function Production and release of cortisol controlled by CNS through sensitive negative feedback loops

Difference between Cushing syndrome and Cushing disease

-Cushing disease is caused by a pituitary gland tumor (usually benign) that over-secretes the hormone ACTH, thus overstimulating the adrenal gland's cortisol production. -Cushing syndrome refers to the signs and symptoms associated with excess cortisol in the body, regardless of the cause.

***ACTH Stimulation Test*** -D/C what drug(s) (except for)? How long prior to test? -Give ______ mcg ACTH, then measure cortisol levels at 30 and 60 minutes - Results: Normal plasma cortisol level is > _____ mcg/dl - Absolute Adrenal Insufficiency if (low or high) baseline cortisol with a positive ACTH stimulation test - Relative Adrenal Insufficiency if (low or high) baseline cortisol with a positive ACTH stimulation test.

-D/C all steroids (except dexamethasone) 24 hours prior to test -Give 250 mcg ACTH -Normal plasma cortisol level > 25 mcg/dl *Absolute AI* -low baseline cortisol with a positive ACTH stim. test *Relative AI* -higher baseline cortisol but with a positive ACTH stim. test

*** Secondary Adrenal insufficiency: - Failure in elaboration of CRH or ACTH secondary to disease or suppression of ______ Most common causes of secondary adrenal insufficiency? (2)

-Failure in elaboration of CRH or ACTH secondary disease, or suppression of the hypothalamic-pituitary axis. (Gland stimulation) -Pituitary surgery or irradiation* -*Use of exogenous glucocorticoids** (produces negative feedback on HPA)

Dexamethasone suppression test: how is it performed?

-Give nighttime dose of dexamethasone, measure cortisol levels in morning.

*Corticosteroid toxicities* Mineralcorticoid effects

-Hypokalemic, hypochloremic alkalosis with HTN -Potential for heart failure in cardiac disease

Cortisol and exogenous steroids produce feedback inhibition on: (3)

-Synthesis of cortisol -Secretion of CRF at hypothalamus -Secretion of ACTH at anterior pituitary

***Cushing syndrome: ACTH Independent pathophysiology - Excessive production of cortisol by abnormal adrenal tissue causes syndrome and suppresses CRH and ACTH release by the hypothalamus and pituitary. -Caused by what what problems with the adrenal gland (2)?

-Tumors of the adrenal gland -Nodular hyperplasia of the adrenal gland

Adrenal insufficiency s/s (5)

-Weakness -Fatigue -Weight loss -Hypotension -Inability to maintain fasting blood glucose

***Cushing syndrome: ACTH Dependent pathophysiology - High plasma ACTH stimulate excessive cortisol production by the adrenal gland. - 70% is due to ________, which is Cushing's disease. -May also be caused by?

-~70% due to pituitary microadenomas = Cushing's Disease -May also be caused by ectopic ACTH producing tumors

21 beta Hydroxylase defect leads to... (3)

1. *21 beta hydroxylase* deficiency leads to decreased cortisol production and build up of androgens 2. Lack of cortisol eliminates the normal negative feedback inhibition of ACTH 3. Gland becomes hyperplastic from excess ACTH stimulation

Functions of Cortisol: 1. Facilitates the synthesis and action of ______ 2. Modulates the synthesis, regulation, coupling, and responsiveness of what receptor? 3. Contributes to normal ______, ______, ______

1. *Facilitates catecholamine synthesis* and action 2. Modulates β-receptor synthesis, regulation, coupling and responsiveness 3. *Contributes to normal vascular tone, permeability, and cardiac contractility*

***Risk for HPA axis suppression:*** 1. Patient is not at risk if taking < _____ mg/day of prednisone 2. Patient is definitely at risk and requires supplementation if taking > ______ mg/day for more than _____ weeks in the past year 3. Patient probably needs supplementation if: -prednisone is in between the doses above -topical steroids > 2 g/day -inhaled steroids > 0.8 mg/day

1. < 5 mg/day (in morning) 2. > 20 mg/day for more than 3 weeks in the past year

Primary Hyperaldosteronism (Conn's syndrome): 1. Typically results from excessive production of aldosterone due to what? 2. Symptoms (3) 3. Ongoing renal loss of potassium leads to? (2) 4. Treatment? (2)

1. Aldosterone by an adrenal adenoma 2. Symptoms: HTN, weakness, tetany 3. Hypokalemic metabolic alkalosis and elevated sodium 4. Spironolactone (competitve aldosterone antagonist) and potassium replacement

Other effects of Glucocorticoids: (8) - Psych? - Neurovascular? - Suppression of what gland in brain? - GI? - Fat? - Vitamin D induced calcium absorption? - Renal? - Surfactant?

1. Behavioral changes: Initial insomnia/euphoria and ultimately depression 2. Psuedotumor cerebri: unknown cause 3. Pituitary suppression: Decreased ACTH/ GH/ LH/ TSH 4. Peptic ulcer disease: d/t inhibition of COX. Possibly related to decreased immune response against H. pylori 5. Fat redistribution: Increased visceral, facial, nuchal, and supraclavicular fat 6. Decreased vitamin D induced calcium absorption: Osteoporosis 7. Physiologic concentrations required for adequate renal function 8. Promotion of surfactant in the near-term fetus

An acute adrenal crisis (Addisonian crisis): 1. May be life threatening due to what? 2. Is this crisis primary or secondary adrenal insufficiency 3. How do we treat it?

1. Circulatory collapse 2. Can be either Primary or secondary 3. With *immediate* treatment with Glucocortioid (hydrocortisone) + mineralcorticoid You start giving mineralcorticoid once glucocorticoids are tapered back

Pharmacokinetics of Cortisol Highly protein bound: 1. Cortisol is 90% bound to what specific protein: 2. It is also bound to ______, but there is very low affinity to this specific protein. 3. At high serum levels of cortisol, CBG becomes saturated, so the level of free cortisol does what?

1. Corticosteroid binding globulin (CBG) ~90% 2. Albumin ~5% 3. Increases significantly

STIMULATION OF FETAL LUNG MATURITY: 1. Lung maturation and production of surfactant is stimulated by what? 2. High dose of what medication class to mother improves lung function in infants delivered prior to 34 weeks gestation? 3. Specific drug used for treatment? How many doses and how far apart are doses?

1. Cortisol 2. Glucocorticoids 3. Betamethasone; 2 doses 24 hours apart

CATABOLIC AND ANTI-ANABOLIC EFFECTS OF GLUCOCORTICOIDS: Glucocorticoid EXCESS leads to what effects on: 1. Muscle? 2. Skin? 3. Bones? 4. Growth in children? 5. Fat?

1. Decreased muscle mass and weakness 2. Thinning of the skin 3. Osteoporosis 4. Delayed growth in children. (Used to be treated with high dose growth hormone) 5. Truncal obesity due to redistribution of fat

Surgery/Anesthesia and the HPA axis: 1. What might postpone the usual intraoperative glucocorticoid surge? 2. Major surgery may increase cortisol release by how much

1. Deep general anesthesia or adequate regional anesthesia 2. 5 fold *POSTPONED, as in, it's still comin so watch out*

***Corticosteroid toxicities: (8)*

1. Iatrogenic Cushing's syndrome 2. Behavioral changes 3. Hypomania or acute psychoses 4. Peptic ulcers 5. Masked infection 6. Cataracts 7. Growth suppression 8. Benign intracranial hypertension (psuedotumor cerebri)

Glucocorticoids: Metabolic Effects: -Important for the maintenance of adequate serum glucose levels in the fasting state: What are 4 ways this is accomplished?

1. Increase serum glucose levels 2. Inhibit glucose uptake by muscle 3. Stimulate lipolysis 4. Catabolic effect on muscle leading to release of amino acids

The adrenal cortex secretion is in response to ACTH from the anterior pituitary: 1. Zona glomerulosa secretes ? 2. Zona fasciculata secretes ? 3. Zona reticularis secretes ?

1. Mineralocorticoids 2. Glucocorticoids 3. Androgens

Who needs preoperative glucocorticoid coverage? (3)

1. Pts with positive ACTH stimulation test (duh) 2. Pts with known adrenal insufficiency (duh) *3.* Pts at risk for HPA axis suppression or adrenal insufficiency based on current or prior glucocorticoid therapy.* (This takes some investigative work, so ask the damn patient!!)

KEY POINT It may take how long for adrenocortical function to return to normal after exogenous steroid use? Why is this important from an anesthesia perspective?

6-12 months This is important to our understanding of which patients need additional glucocorticoid coverage in the perioperative period

***Return of HPA axis function: - Hypothalamic-pituitary function returns more quickly than adrenocortical function. How long can it take for the adrenal glands to fully recover?

6-12 months.

A normal dexamethasone suppression test if a cortisol level < _____ mcg/dl AND ACTH (increase or decrease) A normal test shows that dexamethasone produces negative feedback on ACTH secretion with subsequent drop in cortisol.

<3 mcg/dl and ACTH decrease

An abnormal dexamethasone suppression test is positive for Cushing's syndrome. This result will show a cortisol level > ______ mcg/dl and ACTH (increase or decrease) An abnormal test shows that the ACTH secreting tumor is not inhibited by dexamethasone so cortisol levels remain elevated.

>5 mcg/dl and ACTH still elevated.

KEY POINT Adrenal _____________ may be either primary or secondary, with secondary most commonly the result of (endogenous/exogenous) glucocorticoid use

Adrenal insufficiency Exogenous

The adrenal gland has two areas, the adrenal medulla (inner region) and the adrenal cortex (outer region). The adrenal cortex secretes mineralocorticoids, glucocorticoids, and androgens. What does the adrenal medulla secrete?

Adrenal medulla secretes epinephrine and norepinephrine

KEY POINT What test is used to find the presence of Adrenal insufficiency?

Adrenocorticotropic Hormone (ACTH) stimulation test

What are the three Mineralocorticoids?

Aldosterone Deoxycorticosterone Fludrocortisone

***In general, what are the three primary steroids released by the adrenal cortex?*

Aldosterone (mineralocorticoid) Cortisol (glucocorticoid) Dehydroepiandrosterone (DHEA) (Androgen)

***Classic definition of Adrenal Insufficiency*** - Baseline plasma cortisol level < ______ mcg/dl AND - Cortisol level < ______ mcg/dl after an ACTH stimulation test

Baseline plasma cortisol level < 20 mcg/dl, and Cortisol level < 20 mcg/dl after an *ACTH stimulation test*

MINERALOCORTICOID ANTAGONISTS: - Main drug?

Compete with aldosterone for it's receptor *Spironolactone* - Useful in the diagnosis, and surgical preparation in patients with primary hyperaldosteronism -Also an androgen antagonist - used to treat Hirsutism

Hypothalamic-Pituitary-Adrenal Axis In response to stress, the hypothalamus releases _______ (a hormone) which causes the anterior pituitary to release ________ (a hormone), which stimulates the adrenal cortex to release mineralocorticoids, glucocorticoids, and androgens Negative feedback is used to monitor the amount of hormones needed to be released by the hypothalamus and anterior pituitary

Corticotropin-releasing hormone (CRH) Adrenocorticotropic Hormone (ACTH)

KEY POINT Hypercortisolism is also known as ______________. It can either be ACTH dependent, most commonly due to a ____________, or ACTH independent, due to abnormalities of the ______ gland.

Cushing's Syndrome Pituitary adenoma adrenal gland

The general mechanism of steroids is to alter the ______ of cells. This process is fast or slow?

DNA Slow

What test is used to diagnose Cushing's syndrome?

Dexamethasone suppression test

Diagnosis and Treatment of 21 beta Hydroxylase CAH Measurement of pregnanetriol, a metabolite of ________, in the urine. Increased level of _______ after ACTH stimulation.

Diagnosis -Measurement of pregnanetriol (metabolite of 17-hydroxyprogesterone) in the urine -17-hydroxyprogesterone levels will be increased after ACTH stimulation -Treatment involves maternal dexamethasone (Provides exogenous restoration of normal neg. FB on pituitary to decrease ACTH secretion)

Glucocorticoids (directly/indirectly) inhibit the Cyclooxygenase pathway and (directly/Indirectly) inhibit the Leukotrine pathway

Directly Indirectly

GUIDING PRINCIPLES OF STEROID THERAPY FOR NON-ADRENAL DISORDERS In many instances (i.e. asthma), corticosteroids do not cure but merely reduce symptoms. 1. What are general dosing recommendations? 2. What tests should be obtained prior to starting therapy? 3. Use with caution in those with? (4)

Dosing recommendations: -Minimize dose -Alternate day therapy -Avoid abrupt discontinuation/dose reduction 2. CXR; TB test. (Can reactivate shingles & TB) 3. Diabetes, Peptic ulcer disease, Osteoporosis, Psychiatric illness

MINERALOCORTICOID ANTAGONISTS: - This drug is more highly selective for aldosterone receptor than spironolactone - No androgen receptor effects

Eplerenone

***Cushing's Syndrome is an excessive release of _______

Excessive glucocorticoid release types: -ACTH dependent -ACTH Independent

What is the treatment of adrenal insufficiency?

Glucocorticoid + Mineralocorticoid GC acute phase, MC long term

***10-20% of expressed genes in a cell are regulated by ___________ ***

Glucocorticoids

Glucocorticoids: Metabolic Effects: Glucocorticoids are required for ________(a process that takes place mostly in the liver) -There are multiple, sometimes opposing, effects on protein, fat , and carbohydrate metabolism

Gluconeogenesis

Why is giving a morning dose of corticosteroid better than at night time?

Has less impact on the endogenous release of cortisol

Deoxycorticosterone has mineralocorticoid activity, resulting in: (2)

Hypertension Hypokalemia

Glucocorticoids: Anti-Inflammatory and Immunosuppressive Effects Immunosuppression?

Immunosuppression: 1.) Inhibit tissue macrophages and lymphocytes 2.) Decreased phagocytosis 3.) Decreased production of tumor necrosis factor, interleukin-1 and other substances important in cellular immunity

Glucocorticoids: Anti-Inflammatory and Immunosuppressive Effects *-Anti-inflammatory effects* (6)

Inflammation: 1.) *Reduction in leukocyte infiltration* 2.) *Suppression of inflammatory cytokines and chemokines* 3.) *Decrease in lymphocytes, monocytes, eosinophils and basophils* 4.) *Inhibit phospholipase with resulting decrease in PGs, leukotrienes, and PAF* 5.) *Inhibition of cyclooxygenase and subsequent decrease in PG synthesis* 6.) *Decrease histamine release and associated increase in capillary permeability*

Pharmacokinetics of Cortisol - Primary metabolism takes place where?

Liver

Treatment of Congenital Adrenal Hyperplasia due to 21 beta hydroxylase?

Maternal dexamethasone

Glucocorticoids inhibit _____________ which is needed for arachidonic acid production and subsequent COX/LOX pathways

Phospholipase A2

While the secretion of mineralocorticoids is controlled by the pituitary, they are more importantly controlled by what system?

Renin-angiotensin-aldosterone system

General dosing guidelines of corticosteroids: - To suppress ACTH? -Anti-inflammatory effect or in allergic reactions? -Long term treatment?

Suppress ACTH: -Desire constant level so seek slowly absorbed preparations or use small, frequent doses Anti-inflam allergic reactions: - Fewer, larger doses may be more effective Long term: -Alternate day dosing following initial control (*Results in fewer side effects with equal efficacy*) -Medium acting preparation with minimal mineralocorticoid activity -Best given as a single morning dose

What is one of the most potent stimulators of the HPA axis? What hormone levels increase significantly with surgery? (3)

Surgery CRH, ACTH and cortisol lvls

11 beta Hydroxylase CAH treatment

Treat like acute adrenal crisis.(Give GC followed by MC)

ADRENOCORTICAL ANTAGONISTS: Aminoglutethimide - Blocks conversion of cholesterol to ______. This reduces the synthesis of all hormonally active steroids. - Has been used in the past to decrease estrogen production to treat breast cancer

blocks conversion of cholesterol to pregnenolone

KEY POINT The (glucocorticoids or mineralocorticoids) are critical to maintaining homeostasis, being responsible for the regulation of __________% of expressed genes

glucocorticoids 10-20%

*** How does the use of exogenous glucocorticoids cause secondary adrenal insufficiency

negative feedback on the hypothalamic-pituitary axis

A high cortisol level and low or normal ACTH indicates a (primary or secondary) source of the elevated cortisol

primary

Cushing's Syndrome (Hypercortisolism) S/S (10)

s/s: -Plethoric face -Truncal obesity -Fat redistribution -Muscle wasting -Poor wound healing -Easy bruising -Purple striae -Osteoporosis -Hypertension -Psuedotumor cerebri

Aldosterone plays a role in retaining _____

salt

What 3 "zona's" make-up the adrenal cortex

zona glomerulosa zona fasciculata zona reticularis