L12. Steroid Therapy

What is the location of the hypothalamus, pituitary gland, and adrenal glands respectively?

What is the process by which the adrenal cortex secretes cortisol (and other adrenal steroids)?

Hypothalamic-pituitary-adrenal (HPA) axis --> hypothalamus secretes corticotropin-releasing hormone (CRH) --> this stimulates anterior pituitary gland to secrete adrenocorticotropic hormone (ACTH) --> which stimulates adrenal cortex to secrete cortisol & other adrenal steroids

The hypothalamic-pituitary-adrenal (HPA) axis can be suppressed by what?

endogenous (cortisol) or exogenous glucocorticoids

Sudden withdrawal of long-term exogenous glucocorticoids can result in what?

adrenal insufficiency (therefore you need to taper the dose)

What stimulates the HPA axis?

physical and emotional stress --> increases the production of adrenal steroids to initially enhance body's resistance to stress

what regulates aldosterone?

renin-angiotensin-aldosterone system (RAAS)

**not affected by the HPA axis

What are the two parts of the adrenal gland?

- adrenal cortex
- adrenal medulla

What does the adrenal cortex produce?

corticosteroids

cortex --> corticosteroids

What does the adrenal medulla produce?

- epinephrine
- adrenaline

Which two parts of the adrenal gland makes up 90% of the gland?

adrenal cortex

What are the three zones of the adrenal cortex?

- zona glomerulosa (outer layer)
- zona fasciculata (middle layer)
- zona reticularis (inner layer)

What does the zona glomerulosa produce?

mineralocorticoids (aldosterone) [controls salt balance in body]

What does the zona fasciculata produce?

glucocorticoids (cortisol) [increases blood glucose]

What does the zona reticularis produce?

adrenal androgens (dehydroepiandosterone) [sex]

What is the phrase to remember the zones of the adrenal cortex and their function?

GFR corresponds with salt (mineralocorticoids), sugar (glucocorticoids) and sex (androgens)

"the deeper you go, the sweeter it gets"

Glucocorticoids promote ________ and reduce _______ sensitivity

- promotes gluconeogenesis
- reduces insulin sensitivity

Glucocorticoids promote what that can leads to dorsocervical lipohypertrophy (buffalo hump)?

lipogenesis

How do glucocorticoids affect muscle?

promotes muscle protein catabolism

lymphoid, connective tissue, fat, and skin undergo wasting

What bone disease can glucocorticoids cause?

osteoporosis

Glucocorticoids are anti-_________________.

inflammatory

What do glucocorticoids suppress?

- T-cell activation
- cytokine production
- release of inflammatory mediators by mast cells and eosinophils (histamines, prostaglandins, leukotrienes)

Do glucocorticoids correct underlying diseases?

no, they only limit inflammation

Prostacyclin reduction due to glucocorticoids leads to what?

- decreased capillary permeability
- promotes vasoconstriction --> elevated BP

What circulating blood cells are decreased by glucocorticoids?

- lymphocytes
- eosinophils
- basophils
- monocytes (adaptive immunity)

What circulating blood cells are increased by glucocorticoids?

- erythrocytes
- platelets
- neutrophils (innate immunity)

What are the 5 R's of glucocorticoids?

- Ready innate immune system
- Restore anti-inflammatory state of macs
- Resolve inflammation
- Repress pro-inflammatory factors and adaptive immunity
- Reinforce innate immune response

What does aldosterone (mineralocorticoids) promote the retention of? wWhat does it promote the excretion of?

- sodium retention
- potassium excretion

Where do mineralocorticoids help regulate sodium reabsorption?

excretory sites (+ water follows)

How does aldosterone promote sodium retention and potassium secretion in the kidney collecting duct?

by increasing expression of
1. sodium channels in apical membrane (lumen)
2. sodium/potassium ATPase in basolateral membrane (interstitium)

Explain how corticosteroids affect transcription of genes.

- corticosteroids diffuse into cells and bind to cytosolic receptors
- steroid-receptor complex translocates to nucleus & binds to specific DNA sequence
- binding stimulates/inhibits gene transcription resulting in changes in protein amounts & manifestations of biological effects

What are the two types of receptors?

1. glucocorticoid (GR)
2. mineralocorticoid (MR)

Glucocorticoid receptors are ________ distributed, while mineralocorticoid receptors are distributed where?

broadly

on excretory sites (sweat, salivary glands, kidney, colon)

Glucocorticoid receptors have a high affinity for _________ and a low affinity for _________.

- high affinity for cortisol
- low affinity for aldosterone

What do mineralocorticoid receptors have a high affinity for?

aldosterone and cortisol

______________ can exert both glucocorticoid AND mineralocorticoid actions, but _____________ cannot.

cortisol

aldosterone

Primary adrenal insufficiency is called ________ disease

Addison's disease

What portion of the adrenal gland is destroyed in Addison's disease?

adrenal cortex by autoimmune reactions

Primary adrenal insufficiency causes a decrease in what kinds of hormones?

all classes of adrenocortical hormones

Secondary adrenal insufficiency results from what disorders?

hypothalamic or pituitary disorders (decreases CRH or ACTH production)

Prolonged administration of exogenous glucocorticoids can lead to [primary vs secondary] adrenal insufficiency?

secondary

(negative feedback and inhibition of CRH & ACTH production)

Synthesis of what molecule isn't inhibited by secondary adrenal insufficiency?

aldosterone

(there is a decrease in synthesis of cortisol & adrenal androgens)

What are the most common signs and symptoms of adrenal insufficiency?

- weakness
- weight loss
- increased skin pigmentation
- postural hypotension
- hypoglycemia

What is congenital adrenal hyperplasia?

a group of inherited diseases caused by specific enzyme deficiencies that impair synthesis of cortisol and aldosterone

Congenital adrenal hyperplasia is most commonly caused by a deficiency of what enzyme?

steroid 21-a hydroxylase

Congenital adrenal hyperplasia can lead to an increase of what hormone in the body? What condition does this lead to?

- adrenal androgens (testosterone)
- prenatal virilization (leads to hirsutism in females)

What can you use to treat congenital adrenal hyperplasia?

- hydrocortisone (suppresses ACTH)
- fludrocortisone (provide mineralocorticoid activity)

What is Cushing's syndrome?

adrenocortical hyperfunction (secretion of excessive glucocorticoids)

What condition can lead to the increased production of cortisol (Cushing's)?

ACTH-secreting pituitary adenomas

or cortisol-secreting adenoma or carcinoma of adrenal cortex

What is the most common cause of Cushing's syndrome?

increased production of cortisol due to ACTH-pituitary adenomas

What is iatrogenic Cushing's syndrome?

Cushing's syndrome secondary to pharmacologic treatment with exogenous glucocorticoids, HIV protease inhibitors, etc

Ectopic secretion of ACTH is commonly caused by what?

small cell lung carcinomas

What are common symptoms seen with Cushing's syndrome?

- osteoporosis
- fat deposits on face and back of shoulders
- thin skin
- bruises & petechiae

What are common indications for glucocorticoid therapy in:

replacement of hormone deficiency

acute (medical emergency) vs. chronic adrenal insufficiency, congenital adrenal hyperplasia

What are common indications for glucocorticoid therapy in:

derm conditions

psoriasis (topical only), dermatitis

What are common indications for glucocorticoid therapy in:

pulmonary disorders

asthma, COPD

What are common indications for glucocorticoid therapy in:

autoimmune disorder

RA, multiple sclerosis

What are common indications for glucocorticoid therapy in:

allergic disorders

hypersensitivity and anaphylactic reactions

What are common indications for glucocorticoid therapy in:

cancer

cancer tx, chemo-induced nausea/vomiting

What are common indications for glucocorticoid therapy in:

prevention of organ graft rejection

solid organ transplant

What are common indications for glucocorticoid therapy in:

fetal lung maturation

preterm labor/delivery

What are the top 5 adverse effects of glucocorticoids?

- infections
- osteoporosis
- weight gain
- impaired glucose metabolism
- hypertension

Taking glucocorticoids with a live vaccine has an increased risk of what?

infection due to immunosuppression

Why should you not take desmopressin with glucocorticoids?

it will increase your risk of severe hyponatremia

Glucocorticoids are a substrate for what P450 enzyme? What drugs does it interact with?

CYP3A4
- protease inhibitors (HIV, Hep C)
- Elvitegravir
- Bupropion
- Tacrolimus
- Hormonal Contraceptives
- NSAIDs

What is a contraindication for topical glucocorticosteroids?

open skin lesions (must apply to intact skin)

What is a contraindication for inhaled glucocorticoids?

status asthmaticus (don't use as a rescue inhaler)

Why are there so many different routs of glucocorticoid administration?

to maximize the therapeutic benefit and minimize adverse effects

What is the benefit of giving local administration of drugs?

it delivers high drug concentrations to target tissues while avoiding systemic side effects

What are the different types of systemic administration of drugs?

- oral
- parenteral

What are the different types of local administration of drugs?

- intra-articular (shots in joints)
- topical
- inhalation

Oral administration of glucocorticoids are highly ________ soluble and _______ absorbed

- lipid soluble
- readily absorbed

Are adverse effects common with oral administration of glucocorticoids?

yes (especially with long term use)

Oral glucocorticoids are [expensive vs inexpensive].

inexpensive

When are intra-articular administration of glucocorticoids useful?

in single joint inflammation when systemic absorption is not desired

When is IV administration of glucocorticoids used?

- treat/prevent acute adrenal crisis
- acute allergic reactions
- when oral administration is not feasible (sedated or nausea/vomiting)

**systemic side effects common**

What are topical glucocorticoids used to treat?

skin disorders

What are the benefits of topical administration of glucocorticoids?

delivers high local concentration with very low systemic effects

What are some of the adverse effects of topical glucocorticoids?

local effects like skin atrophy, hypopigmentation, striae

especially at high concentrations, multiple times for day, covering a large BSA, and for >2 weeks @ higher risk of adverse effects and systemic affects

List the topical vehicles of glucocorticoids from most potent to least potent.

ointment > lotion/cream > gel

Drugs with high potency (such as fluocinonide, clobetasol, or halobetasol) should not be used where?

on areas with thin skin, such as the face

When are inhaled corticosteroids used and what is the benefit?

used in allergic rhinitis (nasal) and chronic tx of asthma/COPD

delivers drug directly to nasal passages or airway and lung therefore lower dose is required to control airway inflammation

Inhaled formulations have ________ oral bioavailability.

low oral bioavailability

oral inhalation delivers 20% of dose to lung and 80% is swallowed

swallowed drugs undergo significant first-pass hepatic metabolism, so a very low amount of drug gets into systemic circulation

What are potential adverse effects of inhaled corticosteroids?

oropharyngeal candidiasis and dysphonia

When stopping chronic glucocorticoid therapy, what must you do? Why?

always taper the dose slowly with gradually decreasing doses

long-term steroid therapy suppresses release of hypothalamic CRH & pituitary ACTH resulting in atrophy of adrenal cortex

sudden cessation may induce acute adrenal crisis or exacerbation of underlying inflammatory disease that you must treat with IV glucocorticoids

Since aldosterone (endogenous mineralocorticoid) is not a therapeutic agent due to a high first-pass hepatic metabolism, what do we use instead?

a synthetic (exogenous) mineralocorticoid: fludrocortisone

**has minimal first-pass hepatic metabolism and high mineralocorticoid to glucocorticoid potency ratio of 200:10

What are the indications for fludrocortisone?

1. replacement therapy for primary adrenal insufficiency (Addison's disease)
2. replacement therapy for congenital adrenal hyperplasia

What are the possible adverse effects of fludrocortisone?

hypertension (due to increased salt retention + vasoconstriction)

hypokalemia

heart failure

What are drug interactions with fludrocortisone?

bupropion
furosemide
phenytoin

What are contraindications with fludrocortisone?

desmopressin
live vaccines
systemic fungal infections

What are 4 corticosteroid synthesis inhibitors?

1. ketoconazole
2. metyrapone
3. abiraterone
4. osilodrostat

What is the MOA of ketoconazole and what pathways are affected?

inhibits 17,20-lyase & P450 side chain cleavage enzyme

all active steroids at high doses

What is the indication for ketoconazole?

Cushing's syndrome

What are the possible adverse effects for ketoconazole?

arrhythmia, OTc prolongation, hepatotoxicity

What are the drug interactions for ketoconazole?

• Dofetilide
• Dronedarone
• Methadone
• Ranolazine
• Eplerenone
• Tolvaptan
•Ergot Alkaloids
•Colchicine
•Lurasidone
•Benzodiazepines
(midazolam, triazolam, alprazolam)

**mostly 34A substrates, as ketoconazole is a 34A inhibitor**

What are the contraindications for ketoconazole?

QTc prolonging agents, liver disease, drugs previously mentioned

What is the MOA of metyrapone and pathways affected?

inhibits 11B-hydroxylase

cortisol & aldosterone synthesis

What is the indication for metyrapone?

Cushing's syndrome in pregnant patients

What are the possible adverse events with metyrapone?

HTN, alopecia, hirsutism, rash, adrenal insufficiency, bone marrow suppression (leukopenia), sedation, confusion, withdrawal symptoms

What are the drug interactions with metyrapone?

acetaminophen
5-fluorouracil

What are the contraindications of metyrapone?

adrenal insufficiency