L1- Adrenal pharmacology HPA and RAAS

The adrenal glands consist of two functionally distinct regions. What are they?

• The adrenal cortex (main target for pharmacological therapies)

• The adrenal medulla

What are the three functionally distinct layers (outer to inner) of the adrenal cortex and their products?

• Zona glomerulosa → Mineralocorticoids (aldosterone)

• Zona fasciculata → Glucocorticoids (cortisol)

• Zona reticularis → Sex steroids (androgens)

GFR

GM

FG

GS

What does the adrenal medulla produce? Give two examples

Catecholamines (e.g., adrenaline and noradrenaline)

What regulates adrenal hormone secretion?

• ACTH (pituitary) → cortisol

• RAAS → aldosterone

What are the 3 main functions of cortisol?

• Stress response (↑ Cardiovascular responsiveness)

• Anti-inflammatory and immunosuppressive effects

• Metabolism regulation

C- SAM

What are the 4 metabolic effects of cortisol?

• Increase gluconeogenesis in liver

• Increases glyogenolysis

• Increases lipolysis in muscle

• Increases proteolysis in muscle

What are the 3 cardiovascular effects of cortisol?

• Increases myocardial contractility

• Increases CO

• Increases catecholamine pressor effect

What are the 3 main functions of aldosterone?

• Potassium excretion

• Blood pressure regulation

• Sodium retention

A-PBS

What stimulates the HPA axis? Give 5 examples

Stress

• Hypoglycaemia

• Hypotension

• Fever

• Trauma

• Surgery

What is the pathway of the HPA axis?

Hypothalamus (CRH) → Pituitary (ACTH) → Adrenal cortex → Cortisol

How is the HPA axis regulated?

By negative feedback- cortisol inhibits CRH and ACTH release

What is the purpose of negative feedback in the HPA axis?

To maintain stable cortisol levels

Describe the circadian rhythm of cortisol (graph).

• Peak:

• Lowest:

• Peak: early morning (~6–9 am)

• Lowest: midnight

What controls cortisol’s circadian rhythm?

Hypothalamic signals and the sleep–wake cycle

Why is cortisol’s circadian rhythm clinically important?

Glucocorticoid therapy should mimic this pattern

What are 3 key HPA disorders?

• Addisons disease/ Adrenal insufficiency → inadequate cortisol production

• Cushing syndrome → excess cortisol production

• Drug-induced suppression → risk of long-term glucocorticoid therapy

ACD

What 3 things triggers renin release?

• Low blood pressure/ perfusion

• Low sodium

• Sympathetic activation

Outline the RAAS pathway.

Liver (angiotensinogen) → Renin → Angiotensin I → ACE (lungs) → Angiotensin II

What are the 4 effects of angiotensin II?

• Aldosterone release

• Vasoconstriction

• ↑ ADH from posterior pituitary + thirst from hypothalamus

• ↑ sympathetic activity

What is the main function of ADH?

Water reabsorption in the kidney

What are the 3 primary stimuli for aldosterone secretion?

• Decreased blood volume and hyponatremia (via RAAS activation)

• Indirectly hyperkalemia

Where does aldosterone act in the kidney?

Distal convoluted tubule and collecting duct

MOA of aldosterone

1. Aldosterone binds to mineralocorticoid receptor (MR / NR3C2)

2. The receptor-hormone complex translocates to the nucleus and alters gene transcription

3. It upregulates the epithelial sodium channel (ENaC)

What are the 3 effects of aldosterone at the kidney?

• ↑ Na⁺ reabsorption

• ↑ K⁺ excretion

• ↑ water retention (blood volume)

What is the key difference between HPA axis and RAAS/ADH systems?

HPA is a true endocrine axis; RAAS and ADH are coordinated but not a single regulated pathway- ADH and RAAS work together to maintain fluid balance and blood pressure

What 5 disorders are associated with RAAS?

• Primary hyperaldosteronism

• Secondary hyperaldosteronism

• Apparent mineralocorticoid excess

• Liddle syndrome

• Addison disease

What is the common precursor of all adrenal steroid hormones?

Cholesterol

What is the rate-limiting step of steroidogenesis?

Transport of cholesterol into mitochondria by StAR (steroidogenic acute regulatory protein)

What happens to cholesterol once inside the mitochondria?

It is converted into pregnenolone

Which enzyme converts cholesterol to pregnenolone?

CYP11A1 (cholesterol side-chain cleavage enzyme)

What is the sequence of the first steps in steroidogenesis?

Cholesterol → (StAR transport) → mitochondria → CYP11A1 → pregnenolone

What is pregnenolone the precursor for?

All adrenal steroid hormones

Which enzyme families are mainly involved in steroid hormone synthesis?

Cytochrome P450 enzymes

Name 4 key enzymes involved in adrenal steroidogenesis.

• CYP17

• CYP21

• CYP11B1

• CYP11B2

Which 3 enzymes are required for cortisol synthesis?

• CYP17

• CYP21

• CYP11B1

Which 2 enzymes are involved in aldosterone synthesis?

• CYP21

• CYP11B2

Why are steroidogenesis enzymes important in pharmacology?

They are targets for drugs treating cortisol excess

Which drug inhibits CYP11B1 and what is the effect?

Metyrapone → reduces cortisol synthesis

What type of molecules are steroid hormones?

Lipophilic hormones derived from cholesterol

Are steroid hormones stored in secretory vesicles?

No, they diffuse out once synthesized

Do steroid hormones circulate freely in blood?

No, they are mostly protein-bound to Cortisol-binding globulin (CBG)

Which other protein carries cortisol to a lesser extent?

Albumin

Which fraction of cortisol is biologically active?

The free (unbound) fraction

Where are steroid hormone receptors located?

Intracellular (cytoplasm/nucleus)

What are the 3 main adrenal steroid receptors?

• Glucocorticoid receptor (GR)

• Mineralocorticoid receptor (MR)

• Androgen receptor (AR)

MOA of steroid hormones

Bind receptor → receptor dimerisation → enter nucleus → regulates gene transcription by binding to specific DNA sequences known as hormone response elements

What are the three main domains of nuclear receptors?

• Ligand-binding domain

• DNA-binding domain

• Transcriptional activation domain

What is special about cortisol and MR?

Cortisol can bind MR

Why doesn’t cortisol normally activate MR in the kidney?

It is converted to inactive cortisone

What enzyme prevents cortisol from activating MR?

11β-HSD2 converts cortisol → cortisone (inactive)

What happens if 11β-HSD2 is inhibited? Give 2 effects

Cortisol activates MR → hypertension and hypokalaemia

What substance inhibits 11β-HSD2?

Glycyrrhizinic acid (found in liquorice)

What are the 3 effects of structural modifications on glucocorticoids?

• Increase glucocorticoid activity (duration)

• Alter mineralocorticoid activity

• Increase potency

What is the effect of a double bond in the A ring?

Increased glucocorticoid activity

What is the effect of a CH₃ group at position 6?

Increased glucocorticoid activity

What is the effect of a CH₃ group at position 16?

Increased glucocorticoid activity

What is the effect of fluorine at position 9?

Increased glucocorticoid AND mineralocorticoid activity

What is the effect of CH₃ at C16 + F at C9?

Increased glucocorticoid activity (reduced mineralocorticoid effect)

What is the effect of double bond + CH₃ (C16) + F (C9)?

Increased glucocorticoid activity with almost no mineralocorticoid activity → strong anti-inflammatory effect with minimal salt-retaining effect

Which drug is an example of strong glucocorticoid activity with minimal mineralocorticoid effect?

Dexamethasone

What is the reference glucocorticoid for potency comparison?

Cortisol (potency = 1)

How potent are prednisone and prednisolone compared to cortisol?

~4 times more potent

Which 2 glucocorticoids have ~25× the anti-inflammatory potency of cortisol?

Dexamethasone and Betamethasone

Which corticosteroid has very strong mineralocorticoid activity (Sodium retention)?

Fludrocortisone

What is fludrocortisone mainly used for?

Mineralocorticoid replacement in adrenal insufficiency

Why are dexamethasone and betamethasone preferred in many conditions?

Dexamethasone and Betamethasone have strong anti-inflammatory effect without fluid retention (minimal mineralocorticoid activity)

Which 2 glucocorticoids are short-acting?

Cortisol and cortisone

Which glucocorticoids are intermediate-acting?

Prednisone and methylprednisolone

Which 2 glucocorticoids are long-acting?

Dexamethasone and betamethasone

What is the relationship between potency and duration of action in glucocorticoids?

Higher potency drugs are generally longer-acting

What are glucocorticoids used for? Give 3

•At high-dose (supraphysiologic) anti-inflammatory / immunosuppressive

•Used in inflammatory conditions both systemically and topically

•Immunosuppressive post-transplantation - avoid rejection

Name 4 common conditions treated with glucocorticoids.

• Asthma

• Rheumatoid arthritis

• Inflammatory bowel disease

• Allergic disorders

What are 8 major side effects of glucocorticoids?

•Long-term use - Iatrogenic Cushing’s Syndrome

•Thin Skin / Bruising

•Hypertension

•Osteoporosis

•Proximal Myopathies (muscle weakness)

•Drug-induced Diabetes Mellitus / Insulin Resistance

•Opportunistic Infections

• HPA axis suppressed → Secondary Adrenal Insufficiency if long term glucocorticoids suddenly stopped

What are the three main anti-inflammatory mechanisms of glucocorticoids?

1. Transactivation → ↑ anti-inflammatory proteins

2. Transrepression → ↓ inflammatory gene transcription

3. Post-transcriptional → ↓ cytokine mRNA stability

How do glucocorticoids exert anti-inflammatory effects via transactivation?

Glucocorticoids diffuse into the cell → bind GRα →

complex enters nucleus →

GR homodimer binds GRE →

↑ transcription of anti-inflammatory genes (e.g., SLPI, MKP-1, GILZ)

How do glucocorticoids suppress inflammatory gene transcription (transrepression)?

GR interacts with transcription factors (e.g., NF-κB) and coactivators (CBP)

→ recruits HDAC2 →

histone deacetylation →

↓ transcription of inflammatory genes (cytokines, chemokines, adhesion molecules, inflammatory enzymes)

How do glucocorticoids reduce cytokine production post-transcriptionally?

Glucocorticoids ↑ expression of tristetraprolin (TTP) →

TTP binds AU-rich regions of cytokine mRNA →

promotes mRNA degradation →

↓ cytokine synthesis (TNFa, IL6, GMCSF, COX2)

How is adrenal insufficiency classified?

Primary, secondary, or tertiary (based on level of defect in HPA axis)

What is primary adrenal insufficiency?

Failure of the adrenal gland → ↓ glucocorticoids + ↓ mineralocorticoids (↓ cortisol + ↓ aldosterone)

Name 5 causes of primary adrenal insufficiency.

• Genetic disorders

• Autoimmune adrenalitis

• Metastatic cancer

• Adrenal hemorrhage

• Tuberculosis

What is the most common form of primary adrenal insufficiency?

Addison's disease

What is the treatment for primary adrenal insufficiency (Addison’s Disease)?

Lifelong hormone replacement therapy

• Glucocorticoid replacement

  • Hydrocortisone (15–25 mg/day in divided doses)

• Mineralocorticoid replacement

  • Fludrocortisone (0.05–0.2 mg/day)

When must glucocorticoid doses be increased in treatment of primary adrenal insufficiency?

During stress (infection, surgery, trauma)

What are the 10 symptoms of Addison’s disease?

• Hyperpigmentation

• Low blood pressure

• Weakness

• Weight loss

• Nausea

• Diarrhea

• Vomiting

• Constipation

• Abdominal pain

• Vitiligo

Why does hyperpigmentation occur in Addison’s disease?

↑ ACTH (from lack of cortisol feedback) → stimulates melanocytes

Why do patients with Addison’s disease have low blood pressure?

↓ Aldosterone → ↓ sodium and water retention → ↓ blood volume

What is adrenal crisis?

Life-threatening acute deficiency of cortisol

What can trigger an adrenal crisis? Give 3

• Severe illness

• Trauma

• Abrupt withdrawal of glucocorticoids

What is the 3 step emergency treatment of Adrenal Crisis (Acute Adrenal Insufficiency)?

• IV hydrocortisone (100 mg)

• IV normal saline

• Correction of electrolyte imbalance

What are the 6 symptoms of an Adrenal Crisis (Acute Adrenal Insufficiency)/ Addisonian crisis?

• Fever

• Syncope (severe hypotension)

• Convulsions

• Hypoglycemia

• Hyponatremia (electrolyte imbalance)

• Severe vomiting and diarrhea

What causes secondary and tertiary adrenal insufficiency?

Impaired stimulation of the adrenal cortex due to dysfunction in the HPA axis

What is secondary adrenal insufficiency?

Anterior pituitary failure → ↓ ACTH → ↓ cortisol

What is tertiary adrenal insufficiency?

Hypothalamic failure → ↓ CRH → ↓ ACTH → ↓ cortisol

What is the most common cause of tertiary adrenal insufficiency?

Chronic exogenous glucocorticoid use → atrophy

How do long-term glucocorticoids cause adrenal insufficiency?

Negative feedback → ↓ CRH & ACTH → adrenal atrophy

What happens to aldosterone in secondary/tertiary adrenal insufficiency?

Usually preserved (RAAS intact)

What replacement therapy is needed in secondary/tertiary adrenal insufficiency?

Glucocorticoids only (no mineralocorticoids)

What is the main drug used for replacement therapy in secondary/tertiary adrenal insufficiency?

Hydrocortisone- modified-release hydrocortisone formulations to mimic physiological cortisol rhythm

Name 2 modified-release hydrocortisone formulations used for replacement therapy in secondary/tertiary adrenal insufficiency

• Plenadren

• Chronocort

What is an alternative glucocorticoid for replacement therapy used for replacement therapy in secondary/tertiary adrenal insufficiency?

Prednisolone