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BIOL31571 > Lecture 11 - Synthetic Glucocorticoids - anti-inflammatory agents with side effects > Flashcards

Lecture 11 - Synthetic Glucocorticoids - anti-inflammatory agents with side effects Flashcards

1
Q

Glucocorticoids: what are they, what do they bind to, what do they do, and what are some examples?

A

Cholesterol-derived steroid hormones are synthesised and secreted by the adrenal gland

Glucocorticoid receptors - intracellular nuclear transcription factors

Affect metabolism, inflammation, and the immune system

Cortisol, androsterone, aldosterone, androgens, oestrogen, progesterone, etc

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2
Q

Glucocorticoid receptors: what are they, what is their activation pathway, what are some examples, and what do they do?

A

Intracellular nuclear receptors that act as transcription factors once activated

Glucocorticoid binds leading to activation - dimerisation occurs, they then move to the nucleus and act as TFs

Liver:
* Phosphoenolpyruvate carboxykinase (PEPCK) - transactivation of a gene producing an enzyme that controls the rate of gluconeogenesis
* Tyrosine aminotransferase (TAT) - transactivation of a gene producing an enzyme involved in gluconeogenesis

Adipose Tissue:
* CCAAT/enhancer binding protein (C/EBP) delta (CEBPD) - transactivation of a gene producing a (TF - ER) protein that activates adipogenesis

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3
Q

Glucocorticoid receptor structure

A

AF-1 at its N-terminal - binds co-factors involved in the transcription of the genes it binds to

AF-2 and LBD at its C-terminal - AF-2 also binds cofactors for transcription and LBD is the ligand binding domain

The receptor forms a horseshoe shape such that the N- and C- terminals are near each other

Between the N- and C- terminals, roughly in the middle of the receptor is the DBD (DNA binding domain)

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4
Q

Glucocorticoid receptors: do they only activate genes?

A

No, GRs also inhibit genes

Genes producing the following molecules may be repressed by GRs:
* IL-1β
* IL-8
* IL-4
* IL-5
* TNFα – Tumour necrosis factor α
* GM-CSF – Granulocyte-macrophage colony-stimulating factor
* Osteocalcin

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5
Q

Osteocalcin: what is it, what does it do, what can it clinically be used for, and how do glucocorticoids affect their transcription?

A

Protein involved in bone mineralisation

Marker of bone formation

Glucocorticoids inhibit osteocalcin transcription in osteoblasts by
suppressing Egr2/Krox20-binding enhancer

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6
Q

Glucocorticoid receptor action: how may it affect transcription?

A
  • Binding to GREs - either positively or negatively influencing transcription
  • Binding to cofactors required for transcription - represses TFs that require those cofactors
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7
Q

GRE: what is it, what does it do, and how may glucocorticoids affect it?

A

Glucocorticoid response element

Specific DNA sequence that binds to the glucocorticoid receptor (GR)

GR-GRE binding can either activate or repress transcription

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8
Q

NFκB: what is it, what does it do, and how may glucocorticoids affect it?

A

Nuclear factor kappa B

Group of proteins that control many functions in a cell, including:
* Cell growth and survival
* Immune response
* Inflammatory resoinse
* Cytokine production
* DNA transcription

GR can bind to Jun and Fos, two cofactors required for NFκB action, and prevent TNF gene transcription

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9
Q

NRE: what is it, what does it do, and how may glucocorticoids affect it?

A

Nuclear response element

Involved in transcriptional induction by stimuli that activate NF-κB, such as IL-1, MEKK1, and TAK1

Inhibition of NF-κB action results in reduced NRE action

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10
Q

Glucocorticoid feedback inhibition: what is the process?

A
  • Anterior pituitary gland produces ACTH
  • ACTH promotes glucocorticoid production from the adrenal gland
  • Glucocorticoids cause physiological effects as well as interacting with the pituitary gland
  • Glucocorticoids enter the nucleus of cells, dimerising and binding to and repressing the POMC gene, reducing ACTH production
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11
Q

POMC gene: what is it, what does it code for, and what does it do?

A

Proopiomelanocortin gene

Proopiomelanocortin (POMC)

Produces ACTH after POMC is cleaved

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12
Q

Steroid treatments: how may they be used and what examples are there?

A

Anti-inflammatory agents:
* Arthritis - 56 – 68% of patients treated with GCs (Diurnal Ltd 2015)
* Asthma - 5.4 million people in the UK receiving treatment for asthma (may
not all be steroids)
* Skin disorders

Anti-proliferative agents
* cancer - ie lymphoblastic leukaemia

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13
Q

Steroid treatments: what are some stats?

A

Estimated that 0.5% of population is treated with glucocorticoids (Diurnal Ltd 2015)

In 2018 in UK 41 million prescriptions for GCs in community ie not hospitals

Sales of Steroids:
* European Union - 15 million people take systemic glucocorticoids on an annual basis (Meijer & Periera 2019)
* Globally the corticosteroid market is $4.56 billion in 2021 (ResearchandMarkets.com)
* Use increased in the last 3 years because they have been shown to be beneficial in the treatment of Covid and other corona-viruses due to their ability to modulate the inflammatory response

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14
Q

Steroid treatments: how similar are steroids?

A

Most are extremely similar, with some (such as cortisol and prednisolone) differing solely by the presence of a double bond in one of the rings in the molecule

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15
Q

Mifepristone: what is it and what does it do?

A

It is the morning after pill

Antagonises progesterone at the glucocorticoid receptor

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16
Q

Steroid treatments: what are the observable side effects?

A

Excess glucocorticoids resulting in:
* Truncal obesity
* Glucose intolerance - diabetes
* Hypertension
* Striae, bruising, poor wound healing
* Myopathy
* Osteoporosis
* Buffalo hump on the neck - fat distribution
* Fullness of face
* Acne
* Mental disturbance
* Receding hair
* Hirsuitism (excess body hair), amenorrhea, acne (Women)

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17
Q

Steroid treatments: what are the internal side effects?

A
  • Metabolism
  • Growth effects
  • Eye
  • Bone
  • Cardiovascular effects
  • Hypertension
  • Infections
  • Neuropsychiatric disorders
  • Decreased wound healing
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18
Q

Metabolic side effects of steroid treatment

A
  • Hyperglycaemia, glycosuria and diabetes
    (Type II-like)
  • Inhibition of protein synthesis, enhanced
    catabolism
  • Calcium absorption is decreased in the intestine, probably due to antagonism of vitamin D
  • Re-distribution of fat
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19
Q

Growth side effects of steroid treatment

A

Stunting can occur in children

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20
Q

Ocular side effects of steroid treatment

A

Topical steroids can increase intraocular pressure (occurs in 1/3 of the population) which can lead to glaucoma

21
Q

Osteo side effects of steroid treatment

A

Glucocorticoids increase Ca²⁺ resorption

Increased Ca²⁺ resorption from bone leads to osteoporosis - this occurs in 60% of patients with natural Cushing’s syndrome

22
Q

Cardiovascular side effects of steroid treatment

A

Increased cardiac output and decreased total peripheral resistance in normal subjects

23
Q

Blood pressure side effects of steroid treatment

A

Excess glucocorticoids can lead to hypertension

Hypertension - glucocorticoids affect sodium retention and potassium excretion, resulting in increased blood pressure

24
Q

Immune system side effects of steroid treatment

A

Immune suppression - patients on glucocorticoids vulnerable to infections

25
Q

Neuropsychiatric side effects of steroid treatment

A
  • Alterations in EEG (electroencephalogram)
  • Seizures
  • Minor sleep disorders
  • Psychosis

Disturbances are present in about 1/3 of patients

26
Q

Skin side effects of steroid treatment

A

Decreased wound healing

27
Q

Zones of the adrenal gland: what are they and what do they produce?

A

zona glomerulosa - aldosterone
zona fasciculata - cortisol
zona reticularis - testosterone

28
Q

zona glomerulosa: what part of the adrenal gland is it, what does it produce, and what are the stages of production?

A

Outer zone

aldosterone

Cholesterol - pregnenolone - preogesterone - 11-deoxy corticosterone - corticosterone - aldosterone

29
Q

zona fasciculata: what part of the adrenal gland is it, what does it produce, and what are the stages of production?

A

Middle zone

cortisol

Cholesterol - pregnenolone - progesterone - 17aOH progesterone - II-deoxycortisol - cortisol

30
Q

zona reticularis: what part of the adrenal gland is it, what does it produce, and what are the stages of production? - testosterone

A

Inner zone

Testosterone

31
Q

Low blood pressure due to low fluid: what senses this and what is the process that counteracts this?

A

Kidneys sense low fluid/Na⁺

  • Renin converts angiotensinogen into angiotensin I, promoting fluid retention
  • ACE converts angiotensin I into angiotensin II which acts on the lungs
  • Angiotensin II also promotes fluid retention as well as aldosterone production
  • Aldosterone results in Na⁺ retention
  • Pituitary senses increased Na⁺ levels and releases arginine vasopressin (AVP/ADH)
  • Anti-diuretic hormone (AVP/ADH) increases fluid retention and blood pressure
32
Q

Angiotensin I: what is its precursor, what is the enzyme that causes it to be produced, and what does it do?

A

Angiotensinogen

Renin

  • Constricts blood vessels, which helps maintain blood pressure
  • Triggers the body to intake water and salt (Na⁺)
33
Q

Angiotensin II: what is its precursor, what is the enzyme that causes it to be produced, and what does it do?

A

Angiotensin I

Angiotensin convertin enzyme (ACE)

  • Constricts blood vessels, which helps maintain blood pressure
  • Triggers ADH production - promoting the retention of water and salt (Na⁺)
  • Triggers aldosterone production
34
Q

Aldosterone: what is it produced by, what is its main precursor, what is its receptor, what factors cause its production, and what does it do?

A

Zona glomerulosa - the outer part of the adrenal gland

Cholesterol

Mineralocorticoid receptor

Angiotensin II mainly but also ACTH and hyperkalemia (high K⁺) may

Increases sodium retention in the kidney - important for osmotic balance

35
Q

Angiotensin I: what is its precursor, what is the enzyme that causes it to be produced, and what does it do?

A

Angiotensinogen

Renin

  • Constricts blood vessels, which helps maintain blood pressure
  • Triggers the body to intake water and salt (Na⁺)
36
Q

Adrenal gland: what are the types of disorders?

A

Hyperactivity:
* Cushing’s syndrome - hypercortisolemia
* Sex steroid excess

Hypoactivity:
* Addison’s disease - hypoadrenalism
* Adrenal enzyme defects - CAH

37
Q

Addison’s disease: what is it and what are the clinical features?

A

Loss of adrenal cortex activity - low cortisol, low aldosterone (mineralocorticoid deficiency)

  • Sodium loss - water loss
  • Hypotension/faintness
  • Addisonian crisis with collapse due to fainting from hypotension
  • Weakness
  • Weight loss
  • Lassitude
  • Skin pigmentation - high ACTH levels
38
Q

Addison’s disease: how is it diagnosed, what are the causes, and what are the treatments?

A
  • High ACTH
  • Low cortisol
  • Low aldosterone
  • Low sodium, high potassium, and low blood pressure/fluid volume
  • Can test by seeing if synthetic ACTH causes a rise in cortisol levels - if it doesn’t fix, the adrenal gland is the issue

Bilateral adrenalectomy - removed
Adrenal infarction - closes down
Autoimmune
Idiopathic - unknown cause
Tuberculosis in rare cases

Intravenous saline administered followed by hydrocortisone 2-3 times daily and may need to give glucocorticoids which mimic aldosterone action

39
Q

Why are there high ACTH levels in Addison’s disease?

A

No negative feedback from cortisol - continual ACTH production

40
Q

Why do high ACTH levels cause pigmentation?

A

ACTH has the same sequence as MSH which stimulates melanocytes - ACTH can start stimulating skin cells to produce pigments if ACTH is in too large amounts

41
Q

Adrenal sex steroid excess: how frequent is it, what is it caused by, what types are there, and do they affect different people differently?

A

Rare to get tumour without cortisol causing Cushing’s Syndrome but if the tumour derives from the inner zone then it may happen

Congenital adrenal hyperplasia - defects in enzymes producing aldosterone/cortisol result in increased sex steroid production which eventually causes hyperplasia

Androgens (more common):
* In men - no effect
* in women- virilisation, hirsutism ie frontal baldness, acne, and menstrual disturbance

Oestrogens:
* Men- feminisation-breast development, fat distribution is different, lower muscle mass
* In women - no effect

42
Q

Adrenal enzyme defects: what are the conditions called, what are the types, and how frequent are the defects?

A

Congenital adrenal hyperplasia

Most common is 21-hydroxylase (90%) but 3βHSD and 11β-hydroxylase may also occur

43
Q

CAH: what is it, what is it caused by, what does it do, and what is the process?

A

Congenital adrenal hyperplasia

Adrenal enzyme defects - reducing aldosterone/cortisol production

  • Cause excess sex steroid production and its effects
  • Cause water/salt loss (aldosterone)
  • Hypoglycaemia and other effects (cortisol)

Lack of feedback inhibition from cortisol - increased ACTH production - ACTH promotes adrenal growth, causing adrenal hyperplasia

44
Q

Can you live with no cortisol?

A

no

45
Q

CAH: what are the general clinical features?

A

General features:
* Severely affected neonates can present with salt wasting crisis
* Failure to gain weight, vomiting, dehydration, shock
* Death due to adrenal crisis occurs without
treatment.

46
Q

CAH: what are the clinical features in girls?

A

Clinical features in Girls:
* May be virilised at birth, with clitoral
hypertrophy and varying degrees of
ambiguous genitalia, making assignment of
sex difficult on clinical grounds
* In milder forms, the child may appear
normal at birth, but early growth is rapid so
taller and stronger at age 5-6 years
* Epiphyses fuse early causing short final
height
* Breasts may develop, but menstruation is
absent or infrequent
* Hirsutism may occur

47
Q

CAH: what are the clinical features in boys?

A

Clinical features in Boys:
* Normal genitalia at birth
* High initial growth rate, taller and stronger
than classmates (but short final height)
* Precocious puberty – premature growth of
pubic and axillary hair, large penis
* Small testes, no spermatogenesis

48
Q

CAH: how is it treated?

A

Treatment:
* Hydrocortisone to replace cortisol.
* Fludrocortisone (synthetic mineralocorticoid) to replace aldosterone
* Treatment suppresses androgen hypersecretion and prevents further virilisation
* Boys develop normally, girls may need
corrective surgery
* Genetic counselling is available

BIOL31571 (11 decks)

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