Derm/Otolary/Rheum Exam 1: Week 1 MEDS/Pathways

• Corticosteroids (ex: _______) are drugs that mimic cortisol

• _______ = natural stress hormone made by the body

• Main job → reduce _______ + _______ the immune system

Prednisone, cortisol, inflammation, suppress

Where Cortisol Comes From

• Made in the _______

  • Outer part of the _______

  • They sit on top of _______

adrenal cortex, adrenal gland, kidneys

HPA Axis (How Cortisol is Released)

• Step 1: _______

  • Releases _______ (corticotropin-releasing hormone)

• Step 2: _______

  • _______ tells it to release _______ (adrenocorticotropic hormone)

• Step 3: _______

  • _______ tells it to release _______

Hypothalamus, CRH, Anterior Pituitary, CRH, ACTH, Adrenal Cortex, ACTH, Cortisol

What Triggers Cortisol Release?

• Inflammation & immune activation

• Important inflammatory cytokines:

  • _______

  • _______

  • _______

These activate the _______ → cortisol release

IL-1, IL-6, TNF-alpha, HPA axis

What Does Cortisol Do?

• Main effect: Suppresses the immune system

• It inhibits:

  • _______

  • _______

  • _______

• Result:

  • ↓ inflammation

  • ↓ immune response

lymphocytes, macrophages, neutrophils

How Corticosteroid Drugs Work

• Drugs like _______:

  • Copy cortisol’s effects

  • Used to decrease inflammation

• Dose-Dependent Effects

  • Low doses → Mainly _______

  • High doses → _______

  • Higher doses increase risk of:

    • _______

    • _______

Prednisone, anti-inflammatory, immuosuppressive, opportunistic infections, systemic SEs

Main Treatment Goal: Corticosteroids

• Use:

  • _______ effective dose

  • _______ amount of time

• Why? → To reduce _______ + _______

lowest, shortest, SEs, immunosuppression

Negative Feedback (VERY IMPORTANT)

• Cortisol controls its _______.

• When cortisol levels are high:

  • It inhibits the _______ + _______

• So:

  • ↓ _______

  • ↓ _______

  • ↓ _______

own release, hypothalamus, anterior pituitary, CRH, ACTH, cortisol production

1. _______ activates the HPA axis

• _______ → CRH → ACTH → Cortisol

2. Cortisol _______ the immune system

• That’s why corticosteroids work for inflammatory diseases.

3. Corticosteroids _______ cortisol

• Examples:

  • Prednisone

  • _______

  • _______

4. Cortisol uses _______

• High cortisol tells the body: “We have enough — stop making more.”

Inflammation, Inflammation, suppresses, mimic, methylprednisolone, dexamethasone, negative feedback

_______ + _______ are the 2 physiologic corticosteroids secreted by adrenal cortex

Cortisol, Aldosterone

KNOW IMAGE

Cortisol released under influence of _______

Aldosterone → _______ + _______

Dehydroepiandosterone → _______, weekly-made hormone in both males + females 

ACTH, Ang II, potassium, DHEA

KNOW IMAGE

Corticosteroid: _______ drug that’s based off a hormone produced by the _______

• _______: ↑ glucagongenesis (glucose synthesis) → retain/mimic metabolic effects of cortisol → anti-inflammatory/immunosuppressive agents

• _______: function of Na-K balance → in kidney

  • Fludrocortisone → powerful aldosterone

steroid, adrenal cortex, glucocorticoids, Mineralocorticoids

Glucocorticoid effect mediated by GR (Glucocorticoid Receptor)

• Glucocorticoid (cortisol and glucocorticoid drugs, denoted as S): Acts as _______ on glucocorticoid receptor (GR)

• Glucocorticoid Receptor → _______ (_______) controls gene expression (slow process bc altering function)

• Binding of drug to GR → conformational change + nuclear translocation. 

• Binding to _______ (GRE) → ↑ gene expression of target genes and altered cell function resulting in:

  • Anti-inflammatory + immunosuppressive effect

  • Metabolic effects including lipolysis, gluconeogenesis, protein breakdown.

• Ex. _______

ligands/agonists, TF, nuclear receptor, Promoter Region, Dexamethasone

Glucocorticoids

Receptor location: throughout the body, including the _______

Glucocorticoid Effects

• _______ Actions

• ↑ _______

• ↑ _______ from High levels of Cortisol (preserves _______ while breaking down protein) → more _______ → less _______

brain, anti-inflammatory, gluconeogenesis, protein breakdown, fat, stress, muscle pain

KNOW IMAGE

• _______: examples of prostaglandins (inflammation = ↑ prostaglandins)

• _______:  Inflammatory stimuli → _______ (via downregulation) → _______ → Affected by _______ enzyme to produce prostaglandins

• _______ → determines synthesis of Prostaglandins

Eicosanoids, prostaglandins, Phospholipase A2, arachidonic acid, COX, Phospholipase A2

Effect of Glucocorticoids on Inflammation: Multiple Sites for Inhibition 

KNOW IMAGE

Mineralocorticoid effect mediated by MR (Mineralocorticoid Receptor)

• Mineralocorticoids regulate _______ exchange in the renal _______ with the net effect of _______ reabsorption (and _______ retention) and _______ excretion.

• _______ binds to MR (Mineralocorticoid Receptor)

• ↑ cortisol levels → ↑ _______ retained → ↑ _______ 

• Excess Cortisol → Hypertension Relation?

  • Cortisol has _______ affinities for GR + MR receptors.

  • Syndrome of cortisol excess include _______ retention and _______

Na/K, collecting duct, sodium, water, potassium, aldosterone, water, BP, equal, Na/H2O, HTN

• Anti-Inflammatory Potency → _______ binding

• Sodium-Retaining Potency → _______ binding

GR, MR

• _______ → EQUAL affinity (=1)

• _______ → powerful Na+ retention → used as _______ supplement/replacement (mimics effect)

  • NOT GOOD for _______ agent bc it results in HTN

Hydrocortisone, Fludrocortisone, aldosterone, anti-inflammatory

Adverse Effects (PREDNISONE)

• _______ & _______ effects (delirium, mood swings, euphoria)

• _______ of _______ → ↑ _______

• _______: cataracts, glaucoma

• _______

• _______: HA, insomnia, seizure

• _______; increased appetite

• _______

• _______

• _______

• _______ & _______ changes (↓ __⁺ ↓ __⁺ ↑ __⁺)

PUD, psychiatric, Retention, sodium and water, HTN, Eye, Diabetes, Neurologic, infection, swelling, osteoporosis, nausea, electrolyte, pH, K, H, Na

Long-term effect of supraphysiologic glucocorticoids on HPA axis regulation

• A steroid taper approach is used to avoid precipitating _______ as a result of abrupt treatment discontinuation.

• Oral predisone causes _______ → _______ production is inhibited in the adrenal cortex

adrenal insufficiency, negative feedback inhibition, cortisol

KNOW IMAGE

Both OA + RA → _______

• _______ is supposed to dampen it → but doesn’t always work bc it doesn’t work or inflammation is too strong → overwhelmed

inflammation, cortisol

• _______ → chronic progressive joint disease, involving cartilage loss

• _______ → immune system mistakenly attacks its own tissues, primarily in joint linings → systemic problem

• _______ → wear and tear arthritis → chronic + slowly gets worse

• _______ → not localized pain

OA, RA, OA, RA

_______

• Irreversible loss of articular cartilage (cusions joints) → synovial inflammation + bone thickening (pain and not being able to move well) → progressive loss of joint function

OA

_______

• Autoimmune disease → immune system mistakenly targets synovial tissues in the joints

• Immune cells, especially _______ cells, get activated → produce _______ → release cytokines (_______ → drives chronic inflammation + pannus)

  • Pannus: overgrown synovial tissue that invades + destroys _______ → hallmark of _______

RA, B and T, Abs, TNF-alpha, cartilage and bone, RA

HPA Axis: body’s main stress regulator 

• Feedback loop: Triggered by _______ + _______

  • Hypothalamus releases _______ → tells pituitary to pump out _______ → leads to _______ (adrenal cortex makes it)

  • Stress = cortisol (fights inflammation + suppresses immune cells): lymphocytes/macrophages → reducing inflammation

• Affects metabolism

  • Increases blood sugar

  • Breaks down protein

  • Drugs like Prednisone mimic cortisol (synthetic cortisol)

    • Low-Dose → _______ 

    • High-Dose → _______ → trick the body

IFN-alpha, IL-1, CRH, ACTH, cortisol, anti-inflammatory, immunosuppressive

• Outermost: Zona _______ → where _______ is produced

• Middle/Thickest Layer: Zona _______ → main _______ producer

• Innermost Layer: Zona _______ → produces _______ (_______ precursor, hormone in both males + females)

Glomularosa, aldosterone, Fasciculata, cortisol, Reticularis, DHEA, androgen

Protein Citrullination Detail

• Citrullination = _______ of _______ → citrulline

• Creates abnormal antigens that trigger _______

deamination, arginine, autoimmunity

Immune Complex Formation

• _______ + _______ form immune complexes

• Macrophages recognize immune complexes → more _______

• Prognosis: Higher RF levels = _______ RA

• Missing RA Lab Tests

  • ESR

  • CRP

  • ANA

  • CBC

  • You only included _______ + _______.

RF, IgG, inflammation, more severe, RF, ACPA

Negative Feedback Concept: 

• High cortisol:

  • ↓ _______

  • ↓ _______

  • ↓ _______

Easy idea: “Too much cortisol shuts off the pathway.”

CRH, ACTH, natural cortisol production

Aldosterone controlled mainly by:

• _______

• _______

Ang II, Potassium

Glucocorticoid Receptor (GR) Mechanism

• Glucocorticoids bind _______ glucocorticoid receptor (GR)

• GR is a _______

• Drug binding causes:

  • Conformational change

  • Nuclear translocation

  • Binding to GREs (glucocorticoid response elements)

  • Altered gene transcription

intracellular, nuclear TF

Glucocorticoid Metabolic Effects

• ↑ _______ specifically

• ↑ protein _______

• _______

gluconeogenesis, breakdown, lipolysis

Eicosanoid / Prostaglandin Pathway Details

• You simplified it well, but missing exact pathway:

• Inflammation → _______ → _______ → _______ enzyme → Prostaglandins

• Key Point: _______ determines prostaglandin synthesis

Phospholipase A2, Arachidonic Acid, COX, Phospholipase A2

Mineralocorticoid Details

• Site of Action: _______

• Receptor Name: Mineralocorticoid receptor (MR)

• Electrolyte Effects → Original notes specifically said:

  • ↓ __⁺

  • ↓ __⁺

  • ↑ __⁺

renal collecting duct, K, H, Na

_______ steroids suppress the _______ via _______

Exogenous, HPA axis, negative feedback

Na⁺ retention → _______ retention → ↑ _______

water, BP

_______ prostaglandin levels → glucocorticoid-induced protein that directly inhibits phospholipase A2 → _______ (_______) 

Decreased, annexin-1, lipocortin-1

_______ + _____kalemia + metabolic _______ + bilateral _______ → excess excretion of aldosterone (zona _______) → Regulated by Ang II and K+

HTN, hypo, alkalosis, adrenal hyperplasia, glomerulosa

• Greatest reduction in joint inflammation when on biologic → _______

• Excess aldosterone secretion → _______ serum _______ concentration

  • Zona glomerulosa → _______ production stimulated by potassium

  • Direct activation of this → enhances _______ → pt has hyperaldosteronism (suppressed _______) → _______ + _______

TNF-alpha, high, potassium, aldosterone, aldosterone synthesis, plasma renin, HTN, hypokalemia

What type of receptor is glucocorticoids

• Acts as _______ on GR (_______ receptor)

Drug of cortisol

• _______

Pro-inflammatory cytokines

• IL-_______

• IL-_______

• IL-_______

• _______

What agent is used for its mineralocorticoid activity, NOT for glucocorticoid effects?

• _______

agonists, intracellular nuclear, hydrocortisone, 1-Beta, 6, 17, TNF-alpha, fludrocortisone

Prednisone is ______ (irreversible, agonist, antagonist) to cortisol 

• Mimic effect of cortisol → _______

Dexamethasone (WHAT WAS THE QUESTION?)

• _______ + _______ glucocorticoids

• _______ on GR → translocation to _______ → altering gene expression → _______ + _______ effects

• 25x _______ than cortisol + our hormone → need _______ dose to do same effect as prednisone

• Does NOT activate _______ receptor

GR agonist, powerful, potent, agonist, nucleus, anti-inflammatory, metabolic, more potent, lower, MR