SPR L1 Corticosteroids Flashcards

1
Q

Learning Outcomes

for general perusal

A
  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
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2
Q

Control in Endocrine Hormone Systems

  1. Outline this control
  2. What happens when you give high doses?
A
  1. See picture. Self regulatory system.
  2. you drive the negative feedback and shut down the production of endogenous steroids
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3
Q

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?
A
  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
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4
Q

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?
A
  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)

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5
Q

What is hydrocortisone?

A

Cortisol

The main glucocorticoid

(cortisone is inactive)

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6
Q

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?
A
  1. The adrenal cortex. Mineralocorticoids – Zona G

Glucocorticoids – Zona F.

  1. Glucocorticoid receptor: widely expressed

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

  1. as anti-inflammatory drugs
  2. such as aldosterone regulate electrolyte balance in the kidney (e.g. fludrocortisone used in Addison’s disease)
  3. due to the action of the enzyme 11-b-hydroxysteroid dehydrogenase which inactivates GCs
  4. Activation of the Mineralocorticoid receptor by GCs
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7
Q

Examples of Steroids

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

(endogenous ones in bold)

A
  1. hydrocortisone
    - prednisolone, deflazacort
    - Betamethasone, dexamethasone (potent)
    - Beclomethasone (asthma)
  2. Bind to the Glucocorticoid Receptor in the cytoplasm (widely expressed) Anti-insulin
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8
Q

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?
A
  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
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9
Q

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?
A
  1. Cholesterol
  2. 11-beta hydroxylase
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10
Q
  1. Where are Steroid hormone receptors found?
  2. Outline what happens upon binding
A
  1. in the cytosol
  2. receptor changes shape, becomes active, increases transcription of certain genes involved in immune response
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11
Q

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?
A

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

all steroid receptors consist of modules that perform specific functions

  1. Dimerisation (binds as a dimer, sits on top of the DNA)
  2. 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)

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12
Q

Actions of Glucocorticoids

What are the main actions of glucocorticoids?

A

Metabolic - hydrocortisone

Anti-inflammatory - prednisolone

Immunosuppressive - dexamethasone

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13
Q

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?
A
  1. Addison’s Disease
  2. Cushing’s Syndrome
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14
Q

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?
A
  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)
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15
Q

Clinical use of Glucocorticoids

Outline the main uses

A
  • 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)
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16
Q

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
A
  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)
17
Q

Use of corticosteroids to treat musculoskeletal disease

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

A
  • 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
18
Q

How do corticosteroids reduce inflammation in SLE/RA?

A
  • 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
19
Q
  1. What is Addison’s Disease?
A
  1. Primary Hypoadrenalism, no steroids produced from adrenal cortex
20
Q

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?
A
  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
21
Q

What is the main side-effect of glucocorticoids?

A

suppression of the HPA axis

  • steroids needed for normal immune function
  • high doses of steroids are immunosuppressive/anti-inflammatory
22
Q

Side-effects of corticosteroid therapy

What are ROA dependant side effects?

A
  • Systemic (see figure)
  • Inhaled:
    • oral candidisis
    • increased pneumonia risk
    • increased blood glucose
23
Q

What are the major adverse effects of corticosteroid therapy?

A
  • 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)
24
Q

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?
A
  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)

  1. bone protection together with GC therapy for at risk patients: calcium/bisphosphonate drugs (PODT Musculoskeletal Case 4)
25
Q

Cushing’s Syndrome

How does this arise?

A

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
26
Q

What are the clinical features of Cushing’s Syndome?

A
27
Q

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?
A
  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
  1. 150-300 nmol/L
28
Q

Patient with Cushing’s Syndrome caused by adrenal adenoma

see picture

A
29
Q

When are steroids contraindicated?

Home Reading (PODT Tutorials)

A

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
30
Q

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?
A
  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
31
Q

Key Point: Effects of corticosteroids on muscle mass

Outline these effects in

  1. Addison’s Disease
  2. Cushing’s Disease
  3. Body Builders
A
  1. Adrenal insufficiency

No steroids produced

Weight loss

  1. Excess steroids production

Weight gain (adipose)

Muscle weakness/atrophy

(metabolic effects)

  1. Anabolic Steroids

(Testosterone

Nandrolone

Build Muscle mass)

32
Q

What are other pharmacological options for musculoskeletal disease?

A
  • 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