Chapter 18 - Corticosteroids

Adrenal Gland

A pair of endocrine glands that sit just above the kidneys and secrete hormones that help arouse the body in times of stress

Cortex of Adrenal Gland

subdivided based on histology, enzyme content and secretory products of cells

Parts that make up cortex

- zona glomerulosa

- zona fasciculata

- zona reticularis

Zona Glomerulosa

produces aldosterone

Zona Fasciculata

produces cortisol and small amount of androgens

Zona Reticularis

produces androgens and small amount of cortisol

Medulla

innervated by sympathetic and preganglionic neurons and releases E/NE as part of fight or flight response

Adrenocorticosteroids

steroid hormones derived from cholesterol produced by the adrenal cortex

Mineralocorticoids

enhance water and sodium retention in the kidneys

Glucocorticoids

cause increased glucose availability, decreased inflammation

Androgens

testosterone-like effects

What triggers the release of corticotropin-releasing hormone (CRH)?

neural inputs such as stress

What happens when we have an increase CRH secrtion by the hypothalamus?

increase in plasma CRH -> increased ACTH -> increased plasma ACTH -> increased corisol secretion -> increased plasma cortisol

Increased plasma cortisol action

acts on hypothalamus as negative feedback to inhibit CRH secretion & inhibit the pathway from further occuring & producing excess cortisol

CRH (corticotropin-releasing hormone)

stimulates release of ACTH

ACTH (adrenocorticotropic hormone)

stimulates secretion of hormones by adrenal cortex suhc as cortisol

What occurs with short term stress response?

SNS acted upon, releasing epinehrine & norepinephrine that acts on the body to produce certain reactions

Short term stress response

- heartbeat & blood pressure increase

- blood glucose levels rise

- muscles become energized

What occurs with long term stress response?

release of CRH by neurosecretory cells & ACTH by anterior pituitary gland

Long term stress response - gluccocorticoids

- protein & fat metabolism instead of glucose breakdown (makes sure body has enough fuel circulating in the blood)

- reduction of inflammation; immune cells are suppressed (in order to protect the body & prevent slowing processes)

Long term stress response - mineralcocorticoids

- sodium ions and water are reabsorbed by kidney

- blood volume and pressure increase

Mechanism of Cortisol

- 1. dissociation from cortisol binding globulin

- 2. diffusion into the cell

- 3. binding to glucocorticoid receptors & acts as transcription factor to switch genes on or off

- 4. translocation to nucleus

- 5. binding to glucocorticoid response element

- 6. gene transcription & altered cellular function

Normal homeostatic functions of cortisol

- maintains normal BP through permissive action on smooth muscle catecholamine reactivity

- Maintains levels of metabolic enzymes

- Maintains blood glucose and lipids

- Keeps immune system in check

Cortisol & Circadian Rhythm

secretion follows a circadian rhythm regulated by pulses of ACTH (peak in early morning and after meals)

Pharmacological effects

increased level of these effects, with immune suppression often the desired effect

Key Differentiating Features of Glucocorticoids

- duration of action

- glucocorticoid potency

- mineralcorticoid activity

Glucocorticoid Potency

- potency is measured relative to cortisol

- higher potency = stronger effects at lower doses

- increased is associated with greater risk of adverse effects including HPA suppression

Mineralcorticoid Activity of Glucocorticoids

activate mineralocorticoid receptors result in retaining sodium & water which leads to edema & hypertension

What types of patients do we use minimal mineralcorticoid effects?

- HF

- hypertension

- cerebral edema

Prodrugs

some glucocorticoids require hepatic activation & this is an important consideration in patients with decreased liver function

Physiological Replacement

glucocorticoids can mimic normal cortisol secretion & is used for adrenal insufficiency

Pharmacologic Dosing

supraphysiologic doses are used for anti-inflammatory or immunosuppressive effects

Drug of choice depends on:

- indication (replacement vs. suppression)

- desired duration of action, dosing schedule, & route

- need to minimize salt retention

- risk of HPA axis suppression

- no single glucocorticoid is ideal for all situations

Hydrocortisone (cortisol)

- potency: 1

- moderate activity

- short duration (8-12 hr)

- not a prodrug

Clinical use of hydrocortisone

most physiologic; used for adrenal insufficiency & stress dosing

Cortisone

- potency: 0.8

- moderate activity

- short duration

- prodrug

Clinical use of cortisone

rarely used; requires liver activation

Prednisone

- potency: 4

- low activity

- intermediate duration (18-36 hr)

- prodrug

Clincal use of prednisone

most commonly prescribed oral steroid

Prednisolone

- potency: 4

- low activity

- intermediate duration

- not a prodrug

Clinical use of prednisolone

active form of prednisone; preferred in liver disease because liver does not have to activate it like it does for prodrugs

Methylprednisolone

- potency: 5

- minimal activity

- intermediate duration

- not a prodrug

Clinical use of methylprednisolone

common IV steroid; medrol dose packs

Triamicinolone

- potency: 5

- minimal activity

- intermediate duration

- not a prodrug

Clinical use of triamicinolone

often intra-articular or topical

Dexamethasone

- potency: 25

- no mineralcorticoid activity

- long duration (36-73 hr)

- not a prodrug

Clinical use of dexamethasone

very potent, no salt retention; used in cerebral edema & suppression testing

Betamethasone

- potency: 25-30

- no mineralcorticoid activity

- long duration

- not a prodrug

Clincal use of betamethasone

similar to dexamethasone; specifically sued for fetal lung maturation

Fludrocortisone

- potency: 10 (weak GC)

- very high activity

- intermediate duration

- not a prodrug

Clinical use of fludrocortisone

primarily mineralcocorticoid (addisons disease)

Glucocorticoids suppress ______

immune function

Considerations for patients taking glucocorticoid - immune functions

- increased susceptibility to bacterial, viral, fungal, & opportunistic infections

- may mask typical signs of infection

- use caution in immunocompromised patients

- assess for active infection before initiation of drug

- distinguish inflammation before treating

- monitor closely for infections during therapy

Catabolic Effects & Tissue Healing

glucocorticoids are catabolic so they decrease collagen synthesis & therefore delay wound healing/promote muscle wasting & bone loss which may result in slower recovery from injury/surgery

HPA Axis Suppression & Stress Response

chronic use suppresses the HPA axis

Dosing & Duration

adverse effects are tied to dose & duration of treatment; it is usually safe to stop without tapering off the drug during short term use, but with long term use you want the smallest effective dose, avoid high doses chronically, & consider tapering schedule

Adverse Effects

- musculoskeletal

- metabolic/endocrine

- opthalmologic

- cardiovascular

- GI

- immunosuppression

- neuropsychiatric

Musculoskeletal

- muscle atrophy

- osteoporosis

- osteonecrosis

Metabolic/Endocrine

- weight gain

- hyperglycemia

- HPA suppression

Opthalmologic

cataracts & glaucoma

Cardiovascular

- hypertension

- edema

- increased ASCVD risk

GI

- ulcers

- bleeding

Immunosuppression

increased susceptibility to infections

Neuropsychiatric

- euphoria

- insomnia

- depression

- psychosis

Cushing Syndrome

condition caused by excess cortisol that causes longerm steroid use (iatrogenic), pituitary tumors, and adrenal gland tumors

Dexamethasone Suppression Test

evaluates the body's cortisol regulation where a low dose or high dose of the steroid is administered in the evening & cortisol is measured the next morning

Low-Dose Test Result

used to screen for Cushing's Syndrome; in normal individuals will suppress cortisol levels but abnormally high cortisol production would indicate issue

High-Dose Test

used to differentiate the cause of Cushing's syndrome; high dose will suppress cortisol in the disease while no respoonse suggests ectopic ACTH production