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PMCOL 200 > Glucocorticoids and Immunopharmacology > Flashcards

Glucocorticoids and Immunopharmacology Flashcards

This deck information has been obtained from the University Of Alberta - please do not post this information in websites/etc. -- it will be a violation

1
Q

Glucocorticoids

A
  • steroid hormones widely used for the treatment of inflammation, metabolic disorders autoimmune diseases, and cancer

Ex. cortisol made in the Zona Fasciculata

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2
Q

Adrenal cortex

A
  • The adrenal cortex is divided into three components:
    Zona Glomerulosa -ZG, Zona Fasciculata -ZF, Zona Reticulates –ZR
  • Steroid hormones production occurs in the adrenal cortex
  • sits on top of each kidney (gland component made up of the medulla and the cortex)
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3
Q

Mineralocorticoids

A
  • A class of steroids that regulate salt and water balance
  • They are produced in the adrenal cortex and control the activity of sodium and potassium channels in the kidney tubules, which affects the reabsorption of salt and water
  • Example –> Aldosterone made in Zona Glomerulosa
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4
Q

Cortisol

A
  • Cortisol is a steroid hormone that is produced by your adrenal glands
  • When you are stressed, increased cortisol is released into your bloodstream
  • Having the right cortisol balance is essential for your health, and producing too much or too little cortisol can cause health problems
  • increases circulating sugars (glucose) in the bloodstream, enhances your brain’s use of glucose and increases the availability of substances that repair tissues
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5
Q

Aldosterone

A

Regulate salt and water balance in the kidneys

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6
Q

HPA axis

A
  • Controls the release of cortisol from the ZF
  • reacts to the stress

1) Hypothalamus releases CRF Hormone (CRH)
2) The hormone than acts on the pituitary, which releases ACTH
3) ACTH than stimulates the adrenal gland to secrete cortisol
4) The adrenal gland secretes cortisol which acts on the different target tissues to elicit stress-related symptoms

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7
Q

Hypothalamus

A

controls the release of hormones from the pituitary gland

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8
Q

Pituitary gland

A

A hormone secreting gland located below the hypothalamus, which releases a variety of hormones form the bloodstream

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9
Q

General mechanism of action of a steroid hormone

A
  1. In the cell cytoplasm, the receptor is bound to a heat shock protein 90
  2. Binding of the steroid, causes the heat shock protein 90 to leave the steroid
  3. The receptor bound steroid dimerizes
  4. It travels into the nucleus
  5. This induces the transcription of targeted genes
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10
Q

Glucocorticoid receptor

A

Stimulate GC responses

Ex. Dexamethasone, Cortisol, Prednisone

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11
Q

Mineralocorticoid receptor

A

Stimulate MC responses

Ex. Fludrocortisone, Cortisol, Aldosterone

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12
Q

Steroid affinities

A

Steroids have different affinities for either receptor

Each receptor activates/represses transcription of different sets of genes – unique target tissues

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13
Q

11-beta-hydroxy-steroid dehydrogenase Type 1

A

Many glucocorticoid target tissues – adipose, muscle, liver, etc.

The enzyme converts inactive cortisone into active cortisol

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14
Q

11-beta-hydroxy-steroid dehydrogenase Type 2

A

Many glucocorticoid target tissues – adipose, muscle, liver, etc.

The enzyme converts active cortisol into inactive cortisone

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15
Q

Pseudohyperaldosteronism

A

The diseases arises from mutations in the 11β- hydroxysteroid dehydrogenase, type 2 gene

This allows glucocorticoids to have an inappropriate effect in aldosterone target tissues like the kidney… can cause high blood pressure (due to aldosterone-like effects including Na+ and water reabsorption)

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16
Q

Lipocortin/annexin

A
  • large family of proteins characterized by ‘annexing repeats’
  • Inhibit phospholipase A2, one of the first links in the arachidonic cascade and a principal agent in the inflammatory reaction
  • prevents Archadonic Acid generation, and thereby suppression downstream generation
  • Direct effects on Leukocytes – WBCs
  • inhibits their tissue infiltration
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17
Q

Phospholipase A2

A

Converts phospholipids to arachidonic acids

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18
Q

Cyclooxyrgenase 2 –COX2

A
  • It is an important inflammatory mediator, early in the process of inflammation
  • It plays an early step in the metabolism of Arachidonic Acid to various prostanoids (depending on the cell type)
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19
Q

How do glucocorticoids act on COX2?

A

They influence the transcription of the COX-2 gene, leading to a long-term suppression of COX-2 expression (protein levels)

20
Q

Addison’s disease

A
  • Chronic adrenocotical insufficiency
    Symptoms can include –> fatigue, sugar imbalance problems, skin discolouration
  • Low production of glucocorticoids, and often mineralocorticoids
  • Typically treated with GC/MC supplementation (hydrocortisone/cortisol)
21
Q

Why discolouring in Addison’s disease?

A
  • ACTH is generated in POMC neurons of the pituitary
  • Cleavage of the POMC gene product generates multiple hormones, including melanocyte stimulating hormone
  • Absence of feedback from cortisol causes hyper-production of POMC and downstream products

POMC – pre-opiomelamocortin – POMC

22
Q

Cushing’s syndrome

A

Adrenal overactivity leading to excessive cortisol

Symptoms include
- round face, fat deposition in trunk
- muscle loss, osteoporosis – protein and bone catabolism
- resection of adrenals or pituitary tumour, followed by gradual adjustment towards a maintenance dose of cortisol

helps understand the features of side effects associated with GC treatment

23
Q

Tapering of therapeutic glucocorticoids (importance, reason)

A

Negative feedback from glucocorticoid administration will suppress CRH and ACTH production

Results in Addisonian crisis: hypoglycemias, hyponatremia, hyperkalemia, and low blood pressure

When stopping long term course of glucocorticoids, you should not abruptly stop taking it –> i.e reduce 25% each time

24
Q

Some extra considerations/clarifications

A

Adrenal tumour –> increased cortisol and decreased ACTH
Pituitary tumour –> increased cortisol and increased ACTH

25
Q

Basiliximab

A
  • “ximab” = Chimeric
  • IgG1… phagocytosis cells recognize this area of the region
  • Binds to CD25 antigen located on the interleukin-2 receptor
  • antagonist for interleukin-2
  • binds to the receptor sites located on interleukin-2

DIRECTLY Inhibits the human cells

26
Q

Alemtuzumab

A
  • “Zumab” …. humanized
  • IgG1…recognized by WBC’s that are phagocytosis (macrophages, dendritic, neutrophil cells)
  • recognizes the CD52 antigen (provides an accessory mechanism of recognizing those cells)
  • destroys healthy and destructive T and B-cells
27
Q

Humanized Antibody

A

Monoclonal Antibodies – the variable antigen region is grown in mice and the rest contains human gene version

28
Q

What are the problems with antibody based therapy?

A

Antibodies are raised in animals (monoclonal is raised in mice), and using these antibodies causes a problem because they are recognized by the immune system and rapidly degraded

29
Q

What is the solution used in antibody based therapy?

A

The solution is to used chimeric or humanized version of murine - mouse - monoclonal antibodies

This will reduce their antigenicity –> increase their lifetime in the body!

30
Q

What are humanized antibodies?

A
  • “umab” or “zumab”
31
Q

What are chimeric antibodies?

A
  • “imab” and “ximab”
32
Q

Azathioprine

A
  • cytotoxic agent
  • it is metabolized to 6-mercaptopurine
  • fraudulent nucleotide
  • interferes with DNA synthesis and DNA transcription processes
  • effective against rapidly dividing cells
33
Q

Cyclophosphamide

A
  • cytotoxic agent
  • alkylating agent
  • leads to cross-linking of neighbouring bases on a DNA strand
  • Disturbs DNA synthesis and transcription
  • most effective against rapidly dividing cells – cancer cells and immune cells during T-cell maturation and etc.
34
Q

What stages are the Adaptive immune system divided into?

A

Induction Phase and The Effector Phase

35
Q

What is the Induction Phase further divided into?

A

Antigen Presenting Phase and clonal expansion and maturation

Antigen-Presenting Phase

  1. Antigen Presenting Phase
    - Antigens are presented from A.P cells to the T-helper CD4 cells (autocrine interleukin 2 loop)

Clonal Expansion and Maturation
2. The T-helper cells mature and divide into T-helper-0 cells
3. T-helper 0 cells divide to T-helper 1 and 2 cells, respectively

Effector Phase

  1. T-helper 1 cells are responsible in making cytokines, activate other macrophages, are cytotoxic (Glucocorticoids inhibit cytokine synthesis) – they act indirectly by inhibiting the gene transcription of COX2 and directly inhibit the Phospholipase A2 in the form of lipocortin
  2. T-helper 2 cells are responsible for maturing into B-cells which create antibodies, etc.
36
Q

Rapamycin/Sirolimus

A

This drug binds to FKBP to form a complex, this complex inhibits mTOR (INDIRECTLY)

This stops the maturation and differentiation stage of T-cells in the clonal expansion and maturation phase of adaptive immunity

It is inhibiting the signalling cascade activated by interleukin-2 by the interleukin-2 receptor

37
Q

What is mTOR?

A

Mammalian Target Of Rapamycin

***Promotes cell growth and proliferation

38
Q

Tacrolimus

A

Inhibits INDIRECTLY calcineurin by binding to FKBP ==> Does not work like Rapamycin…

This prevents NFAT-mediated gene transcription caused by interleukin-2

  • maturation and proliferation of T-cells
39
Q

Cyclosporine

A

Inhibition of calcineurin by the cylophillin: cyclosporin complex

This prevents NFAT-mediated gene transcription caused by interleukin-2

  • maturation and proliferation of T-cells
40
Q

Calcineurin

A

Phosphates – dephosphorylates NFAT

Dephosphorylates NFAT migrates to the nucleus, leasing to expression of interleukin-2

Very early step of the whole adaptive immunity process

41
Q

NFAT

A

Nuclear factor of activated T-cells pathway including the calcineurin-NFAT pathways

42
Q

Graft-versus-host Disease

A

Donor WBC’s – lymphocytes – reacting against host – especially common in bone marrow transplant

43
Q

Rheumatoid Arthritis

A

Auto-immune disease primarily affecting joints – but also other tissues like bonds

“Rheumatoid arthritis, or RA, is an autoimmune and inflammatory disease, which means that your immune system attacks healthy cells in your body by mistake, causing inflammation (painful swelling) in the affected parts of the body. RA mainly attacks the joints, usually many joints at once” - Centres of Disease control and prevention

44
Q

Lupus

A

Multi-organ autoimmune disease
“Immune system attacks its own tissues, causing widespread inflammation and tissue damage in the affected organs” - Centres of Disease control and prevention

Includes:
- rash on the face (look like a butterfly)
- rash and skin problems

45
Q

Ulcerative Colitis

A

T-cell infiltration – auto immune disease

  • Ulcers form in the colon/stomach, etc. ( gastrointestinal tract)
46
Q

Psoriasis

A

Auto-immune disease leading to scaly patches on the skin
- effects the skin (skin diseases)

PMCOL 200 (3 decks)

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