SPR L1 Corticosteroids

Question 1

Learning Outcomes

for general perusal

Answer 1

1. Be able to describe how corticosteroids are released and act on cells
2. Contrast Gluco versus Mineralocorticoid actions using examples
3. Describe the properties of steroids used in the clinic
4. Give details of the uses of steroids to treat rheumatoid arthritis and other muscle/bone inflammation
5. List the common side-effects of steroids, and the features of Cushing’s syndrome

Question 2

Control in Endocrine Hormone Systems

1. Outline this control
2. What happens when you give high doses?

Answer 2

1. See picture. Self regulatory system.
2. you drive the negative feedback and shut down the production of endogenous steroids

Question 3

Hypothalamic-Pituitary-Adrenal (HPA) Axis

1. What regulates the axis normally?
2. What acts as a +ve driver on the hypothalamus?
3. What does this cause?
4. What gives a negative feedback loop?

Answer 3

1. Circadian Rhythm
2. StressC
3. CRH to act +vely on pituitary, and ACTH to act +vely on the adrenal glands to produce cortisol and give tissue actions
4. These tissue actions feedback negatively on the pituitary and the hypothalamus

Question 4

Adrenocorticotrophic hormone (ACTH, corticotrophin)

1. What is this hormone, what is it produced from, and where?
2. What is the action of this hormone?
3. What are these?

Answer 4

1. -39 amino acid hormone generated from POMC in the endocrine pituitary gland
2. Stimulates cortisol release of adrenal hormones
3. ‘Steroids’ Glucocorticoids - metabolic

Mineralocorticods - electrolyte regulating

Weak androgens - androstenedione

(Pro-opiomelanocortin (POMC) is a precursor polypeptide with 241 amino acid residues)

Question 5

What is hydrocortisone?

Answer 5

Cortisol

The main glucocorticoid

(cortisone is inactive)

Question 6

Glucocorticoids versus Mineralocorticoids

1. Where are both produced?
2. Where do they bind in the body?
3. What are glucocorticoids used as?
4. What are mineralocorticoids used as?
5. Why do glucocorticoids have low activity in the kidney?
6. What is Pseudohyperaldosteronism?

Answer 6

1. The adrenal cortex. Mineralocorticoids – Zona G

Glucocorticoids – Zona F.

2. Glucocorticoid receptor: widely expressed

Mineralocorticoid receptor: mainly expressed in epithelial cells in kidney, colon, bladder

3. as anti-inflammatory drugs
4. such as aldosterone regulate electrolyte balance in the kidney (e.g. fludrocortisone used in Addison’s disease)
5. due to the action of the enzyme 11-b-hydroxysteroid dehydrogenase which inactivates GCs
6. Activation of the Mineralocorticoid receptor by GCs

Question 7

Examples of Steroids

1. Give an example of a Glucocorticoid
2. Where does it bind?

(endogenous ones in bold)

Answer 7

1. hydrocortisone
   - prednisolone, deflazacort
   - Betamethasone, dexamethasone (potent)
   - Beclomethasone (asthma)
2. Bind to the Glucocorticoid Receptor in the cytoplasm (widely expressed) Anti-insulin

Question 8

Examples of Steroids

(endogenous ones in bold)

1. Give an example of a Mineralocorticoid?
2. Where does it bind?
3. What are the actions?
4. How can excess MC secretion be managed?

Answer 8

1. aldosterone, fludrocortisone (synthetic)
2. Bind to the mineralocorticoid receptor expressed mainly in kidney, epithelial cells of colon and bladder, regulate electrolyte balance
3. Increased Na+ reabsorption in the distal tubule of the kidney, increased K+ and H+ excretion
4. Spironolactone - K+ sparing agent used in CHF

Question 9

Biosynthesis of corticosteroids and adrenal androgens

1. What is the precursor for all three types? (GC, MC and Adrenal Androgens)
2. Name an important enzyme involved?

Answer 9

1. Cholesterol
2. 11-beta hydroxylase

Question 10

1. Where are Steroid hormone receptors found?
2. Outline what happens upon binding

Answer 10

1. in the cytosol
2. receptor changes shape, becomes active, increases transcription of certain genes involved in immune response

Question 11

Properties of the Glucocorticoid Receptor

1. What is the basic structure of the glucocorticoid receptor?
2. What is key to function of steroid receptors?
3. How does the activated Glucocorticoid Receptor identify its target genes in the nucleus?

Answer 11

1. NH2 - activation domain - DNA binding domain - ligand binding domain - COOH

all steroid receptors consist of modules that perform specific functions

2. Dimerisation (binds as a dimer, sits on top of the DNA)
3. GC receptor dimers bind to specific hormone response elements (HREs) on target genes.

(Any gene with that sequence will be activated by the gluocortoids. Mutations in any of these will change the specificity of the steroid)

Question 12

Actions of Glucocorticoids

What are the main actions of glucocorticoids?

Answer 12

Metabolic - hydrocortisone

Anti-inflammatory - prednisolone

Immunosuppressive - dexamethasone

Question 13

Corticosteroids: Too Little versus Too Much

1. What results when there is a deficiency of corticosteroids?
2. What results when there is an excess of corticosteroids?

Answer 13

1. Addison’s Disease
2. Cushing’s Syndrome

Question 14

Metabolic effects of Glucocorticoids

1. What are the main actions?
2. What are the actions on the liver?
   
   1. What is there a tendancy towards?
3. What can long term use lead to?

Answer 14

1. protecting glucose-dependent tissues (brain and heart) from starvation => effect carbohydrate and protein metabolism
2. decrease glucose uptake and utilization increase gluconeogenesis
   
   1. tendency towards hyperglycemia​
      
      • Decreased protein synthesis, Increased protein breakdown => muscle (Cushing’s Disease)
      • provides amino acids and glycerol for gluconeogenesis
3. Long-term use can lead to fat redistribution (Cushing’s Syndrome)

Question 15

Clinical use of Glucocorticoids

Outline the main uses

Answer 15

• Replacement therapy for Addison’s disease (adrenal failure)
  
  • hydrocortisone (GC), fludrocortisone (MC)
• anti-inflammatory/immunosupressive therapy
  
  • prednisolone, dexamethasone
• asthma: beclometasone (inhalation) EOP 2
• eczema
• allergic conjunctivitis
• rhinitis
• autoimmune disease-rheumatoid arthritis, inflammatory bowel disease
  
  • transplant patients to prevent graft v host reactions
• used in CANCER
  
  • combination with cytotoxic drugs e.g. Hodkins, leukemia
  • reduce cerebral oedema in patients with brain tumor (dex)
  • anti-emetic therapy in conjunction with chemotherapy
  • weight gain to stimulate appetite (cachexia)

Question 16

Pharmacokinetics - home reading

1. When are most steroids active? What other routes of admin are there?
2. How can adverse effects be minimised?
3. What are glucocorticoids bound to in the plasma?
   
   1. What does this protect from?
4. When are steroids inactive?
5. What is the half life and onset of action of hydrocortisone - why?
6. How does inactivation of GC occur in the liver?
7. Which is the most potent GC?
8. Outline the main properties of commonly used corticosteroids

Answer 16

1. When given orally. iv, im, topically, aerosol, drops etc
2. by giving every second day
3. bound to transcortin (aka corticosteroid binding globulin (CBG)) and albumin in the plasma
   1. protects from first pass metabolism
4. when bound to plasma proteins such as CBG
5. half-life of 90 mins, onset of action 2-8 hrs (transcription)
6. by reduction of the C4-C5 double bond
7. Dexamethasone (see picture)
8. (see picture)

Question 17

Use of corticosteroids to treat musculoskeletal disease

Give examples of MSK conditions that GC are used to treat?

Answer 17

• Rheumatoid Arthritis
• Systemic Lupus Erythematosus (SLE)
• Juvenile Idiopathic arthritis
• all autoimmune diseases of joints, connective tissue etc.
• treatment with supraphysiological doses of steroids reduces inflammation

Question 18

How do corticosteroids reduce inflammation in SLE/RA?

Answer 18

• steroids suppress all phases of early inflammation
  
  • calor, rubor, tumor, dolor, (functio laesa)
• decrease in numbers of activated macrophages, T-cells especially T-helper (CD4+) cells
• decreased IL-1, IL-2 production (lymphocyte activators)
• decreased transcription of COX-2, PLA2, IL-2R via inhibition of AP-1, NFkB signalling
• suppression of chronic inflammation
  
  • a) increased annexin-1 (lipocortin) levels in leukocytes, inhibition of phospholipase A2
    
    • reduced arachadonic acid levels
    • reduced prostaglandin, leukotriene levels

Question 19

1. What is Addison’s Disease?

Answer 19

1. Primary Hypoadrenalism, no steroids produced from adrenal cortex

Question 20

Side-Effects/Adverse Drug Reactions of Glucocorticoids

1. What can these usually be attributed to?
2. How does exogenous GC act upon normal H-P-A axis?
3. What needs to be done when GCs are being withdrawn?
4. What should patients carry?

Answer 20

1. large doses and prolonged administration
2. suppress normal H-P-A response to illness
3. withdrawal from GC needs to be phased
4. patients need to carry a steroid card alerting doctors to the fact that they are on steroid therapy

Question 21

What is the main side-effect of glucocorticoids?

Answer 21

suppression of the HPA axis

• steroids needed for normal immune function
• high doses of steroids are immunosuppressive/anti-inflammatory

Question 22

Side-effects of corticosteroid therapy

What are ROA dependant side effects?

Answer 22

• Systemic (see figure)
• Inhaled:
  
  • oral candidisis
  • increased pneumonia risk
  • increased blood glucose

Question 23

What are the major adverse effects of corticosteroid therapy?

Answer 23

• Physiological
  
  • ·Adrenal and/or pituitary suppression

Pathological

• Cardiovascular
  
  • Increased blood pressure
• Gastrointestinal
  
  • Peptic ulceration exacerbation (possibly)
  • Pancreatitis
• Renal
  
  • Polyuria
  • Nocturia
• Central nervous
  
  • Depression
  • Euphoria
  • Psychosis
  • Insomnia
• Endocrine
  
  • Weight gain
  • Glycosuria/hyperglycaemia/diabetes
  • Impaired growth in children
• Bone and muscle
  
  • Osteoporosis
  • Proximal myopathy and wasting
  • Aseptic necrosis of the hip
  • Pathological fractures
• Skin
  
  • Thinning
  • Easy bruising
• Eyes
  
  • Cataracts (including inhaled drug)
  • Increased susceptibility to infection (signs and fever are frequently masked)
• Septicaemia
• Reactivation of TB
• Skin (e.g. fungi-oral thrush)

Question 24

Why do glucocorticoids cause osteoporosis?

1. What is seen with steroid therapy?
2. Why is this the case?
3. What can be done to help?

Answer 24

1. osteoporosis and increased fractures - important to consider when using e.g. prednisolone
2. GCs regulate Ca2+/PO4– metabolism

GCs regulate collagen synthesis by osteoblasts

GCs inhibit Vit D3 induction of genes in osteoblasts

GCs inhibit osteoblasts (bone formation) and activate osteoclasts (digestion of bone matrix)

3. bone protection together with GC therapy for at risk patients: calcium/bisphosphonate drugs (PODT Musculoskeletal Case 4)

Question 25

**Cushing’s Syndrome** ## Footnote How does this arise?

Answer 25

arises from excess circulating glucocorticoids, * mainly caused by increased circulating levels of GC or ACTH * ACTH from pituitary (65 % of cases-Cushing’s Disease) * ACTH from non-pituitary tumor (10 % of cases) * excess secretion of GC from adrenal tumor (25 % of cases =\> suppression of ACTH secretion

Question 26

What are the clinical features of Cushing's Syndome?

Answer 26

Question 27

**Treatment of Cushing’s Syndrome** 1. untreated Cushing’s has a very bad prognosis, why? 2. What needs to be controlled prior to surgery? 3. How can Cushing's Syndrome be treated? 4. What should we aim to reduce cortisol to?

Answer 27

1. death from hypertension, MI, infection and CHF common 2. cortisol hypersecretion (esp. abdominal surgery) - ncreased morbidity and mortality 3. * **_Metyrapone_**: blocker of **11b-hydroxylase** 750 mg-4 g daily divided doses * **_Ketoconazole_**: **inhibits cortisol synthesis**, 200 mg 3 x daily (see picture) * surgical removal of the pituitary/adrenal tumour 4. 150-300 nmol/L

Question 28

**Patient with Cushing’s Syndrome caused by adrenal adenoma** ## Footnote **see picture**

Answer 28

Question 29

**When are steroids contraindicated?** **Home Reading (PODT Tutorials)**

Answer 29

OCULAR CONTRAINDICATIONS * Glaucoma * Cataracts * Herpetic epithelial infections * Acute bacterial or fungal infection * Significant corneal epithelial defect * Unsure diagnosis SYSTEMIC CONTRAINDICATIONS * Peptic ulcer disease * Diabetes/hyperglycemia * Osteoporosis * Renal disease * Immunocompromised * Mental health problems * Pregnancy * Congestive heart failure * Systemic hypertension

Question 30

**Key Point: Physiological versus Pharmacological Effects of Corticosteroids** 1. What are corticosteroids required for? 2. What is Addison's disease, what does this mean for the dose of GC given? 3. How can Anti-inflammatory and immunosupressive effects of steroids be achieved?

Answer 30

1. corticosteroids required for normal immune responses - physiological regulation of immune cell activation 2. Addison’s Disease: absence of steroid production from adrenals: these patients take **physiological doses** of hydrocortisone and fludrocortisone 3. supraphysiological doses to suppress the immunem system via negative feedback/direct inhibition at higher potency

Question 31

**Key Point: Effects of corticosteroids on muscle mass** Outline these effects in 1. Addison's Disease 2. Cushing's Disease 3. Body Builders

Answer 31

1. Adrenal insufficiency No steroids produced Weight loss 2. Excess steroids production Weight gain (adipose) Muscle weakness/atrophy (metabolic effects) 3. Anabolic Steroids (Testosterone Nandrolone Build Muscle mass)

Question 32

**What are other pharmacological options for musculoskeletal disease?**

Answer 32

* NSAIDs: anti-inflammatory drugs with analgesic properties useful in RA * DMARDs: disease modifying drugs that treat the cause of the RA, as opposed to the inflammation

Question 33

Additional Learning Tools

Answer 33

[https://www.khanacademy.org/science/health-and-medicine/endocrine%20system/introduction%20to%20hormones/v/hypothalamus-and-pituitary-gland](https://www.khanacademy.org/science/health-and-medicine/endocrine%20system/introduction%20to%20hormones/v/hypothalamus-and-pituitary-gland) [https://www.khanacademy.org/science/health-and-medicine/endocrine%20system/introduction%20to%20hormones/v/hormone-concentration-metabolism-negative-feedback](https://www.khanacademy.org/science/health-and-medicine/endocrine%20system/introduction%20to%20hormones/v/hormone-concentration-metabolism-negative-feedback) [//www.khanacademy.org](//www.khanacademy.org)