9 - Hypothalamic/Pituitary Drugs and Corticosteroids

Somatropin

• Structure

• Function/purpose

• ADRs

• Recombinant GH hormone

• Binds GH receptors to stimulate IGF-1 release and help people with growth hormone deficiency

• Hyperglycemia due to counter-regulatory effect, and pseudotumor cerebri, aka increased intracranial pressure that shows up as brain tumor symptoms

Octreotide

• Structure

• Function/purpose

• ADRs

• Somatostatin analogue

• To inhibit GH effect, used in cases like acromegaly or to reduce portal hypertension that causes symptoms like esophageal varices(Bleeding in veins near the esophagus because the body has redirected blood from the high pressure liver to these areas)

• Gallstones due to CCK suppression

Dopamine agonists

• Names

• Function/purpose

• ADRs

• Bromocriptine & Cabergoline

• Treats prolactinomas and Parkinson’s

• Nausea and vomiting, can cause fibrosis in the lung

Desmopressin

• Nickname

• Function/purpose

• ADRs

• dDAVP

• Binds V2 receptors at the CCD, allowing more water reabsorption by expressing more AQP2, allowing it to treat Central Diabetes Insipidus where ADH is lacking. It also boosts Von Willebrand factor to allow for more platelet adhesion

• Hyponatremia

Tolvaptan

• Function/purpose

• ADRs

• Vasopressin antagonist, used to treat SIADH, “Syndrome of inappropriate ADH”, so it helps reduce the amount that can bind and reabsorb water

• ADR: Dehydration, hypernatremia

Steroidogenesis

• Starting material

• Key enzymes

• Cholesterol

• 17alpha hydroxylase: Pushes the pathway to cortisol and androgens

• 21beta hydroxylase: Required to make both aldosterone and cortisol

• 11beta hydroxylase: Final step in making cortisol and aldoesterone

Normal daily cortisol secretion in adults

10mg/day

Cortisone

• A form of cortisol used in cells that don’t want cortisol to bind mineralocorticoid receptors

Fludrocortisone

• Structure

• Function/purpose

• Synthetic mineralocorticoid with glucocorticoid activity

• To boost aldosterone and cortisol action, used in Addison’s and moderate/severe CAH cases

Addison’s disease

Primary adrenal insufficiency → No cortisol, no aldosterone → Unable to mount stress response, hyperkalemia, hyperpigmentation

Congenital Adrenal Hyperplasia

21 Beta hydroxylase deficiency → inability to make cortisol and aldosterone → ACTH is boosted due to feedback → Adrenal cortex is overstimulated(hyperplasia) → Cholesterol forced to go down androgen path

Spironolactone

• Structure

• Function/purpose

• ADRs

• Mineralocorticoid receptor antagonists

• Blocks aldosterone receptors → Less ENaC expression, used in primary or secondary aldosteronism to treat hypertension and hypokalemia

• Non-selectiveness → Can bind other receptors

Glucocortiocoid receptor binds ___ before cortisol arrives

• Heat shock protein 90

Cortisol + glucocorticoid receptor complex causes…

• Transactivation and transrepression of glucose response elements and pro-inflammatory genes

How does cortisol impact glucose and insulin?

• Boost gluconeogenesis

• Increases insulin resistance by reducing GLUT4 translocation

Cortisol impact on: fat

• More lipogenesis at the face, trunk, neck

• More lipolysis at the arms and legs

Explain why cortisol causes

• Prox. muscle weakness

• Striae

• Telangiectasia

• Osteoporosis

• Muscle protein catabolism

• Suppressed fibroblast activity and collagen synthesis

• Thin and weak skin reveal the vessels

• Increases osteoclast activity and will suppress osteoblasts long term

Cortisol effect on immune system and inflammation and explain why

• Immune: Suppresses it, reducing lymphocyte function and also decreases all WBCs except neutrophils(but impairs chemotaxis

• Inflammation: Boosts lipocortin-1 which inhibits PLA2, which usually cleaves phospholipids to release arachidonic acid which begin COX/LOX pathways, so we inhibit that

Synthetic glucocorticoid other name

Steroids

Must know steroids:

• Oral: Prednisolone

• IV: Dexamethasone, hydrocortisone, methylprednisolone

Out of the 4 must know steroids, which one IS cortisol?

• Hydrocortisol, and it has a 1:1 glucocorticoid/mineralocorticoid effect

What are the relative potency of gluco/mineralocorticoid effect for the 4 steroid drugs?

1. Hydrocortisone: 1:1

2. Prednisolone: 4:0.25

3. Methylprednisolone: 5:0

4. Dexamethasone: 30:0

A patient is on 20mg prednisolone a day, switch him to IV dexa

• 20mg pred. is 80 mg hydrocortisone

• Dexa is 30x more potent, so 1mg dexa is 30mg hydrocortisone

  • 80/30 = 2.7mg dexa

Why should we worry about these things before administering synthetic glucocorticoids?

1. TB/strongyloides

2. DM

3. Osteoporosis

4. Hypertension

5. GI Ulcers/gastritis

6. Psychological disorders

1. TB/strongyloides: These diseases/parasites stay latent until our immune system is suppressed, so if we suppress our immune system via steroids, they could blow up

2. DM: Steroids boost gluconeogen./insulin resistance

3. Osteoporosis: Can cause fracture risk since steroids make osteoporosis more likely

4. Hypertension: Mineralocorticoid activity of steroids

5. GI Ulcers/gastritis: Steroids will inhibit PLA2 → less prostaglandinds who secrete bicarb to protect the GI

6. Psychological disorders: Receptors exist in the brain and can cause lots of different effects

Why do steroids inhibit the HPA axis, and how?

Because it’s like already having high cortisol in the body, so our body suppresses CRH and ACTH, causing adrenal atrophy

Why can steroids cause alkalosis?

• Because mineralocorticoid receptor activation also sitmulates H+ ATPase activation → Less acid in the body

How do we stop steroid treatment, and why?

• By tapering, around 2.5-5mg prednisolone equivalent every 3-7 days

  • If not, we can have acute adrenal insufficiency where we have severe hypotension, hypoglycemia, and abdominal pain and CNS symptoms

    • We get this insufficiency because the adrenal cortex has been going through atrophy

What is CYP450, what are CYP450 inducers/inhibitors, and how does it relate to steroids, and what is an example?

• CYP450 is a enzyme in the liver that metabolizes drugs to make them easier to eliminate from the body, and many synthetic glucocorticoids are metabolized by these

• Inducers are drugs that boost CYP450 activity and speed up metabolism, while inhibitors will block or slow down the enzyme. This can make steroids get metabolized and cleared either faster(inducers) which lower their effect or slower(inhibitors) which prolong their effect and causing overdose.

Mifepristone typical role and relation to steroids

• Glucocorticoid receptor antagonist → Shuts down it’s effect

  • But it’s main use is actually a progesterone receptor antagonist, used to block progesterone’s action and help with abortion, but can also b