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Clinical Immunology & Viral Pathogens > Immunosuppressants L11 > Flashcards

Immunosuppressants L11 Flashcards

1
Q

What 3 things are immunosuppressive drugs used for?

A
  • Prevent rejection of transplanted organs and tissues (bone marrow, heart, kidney)
  • Treat autoimmune diseases or disease of autoimmune origin myasthenia gravis, systemic lupus erythematosus, Crohns disease)
  • Treat some non-autoimmune inflammatory diseases (allergic asthma, atopic dermititis)
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2
Q

Describe Corticosteroids.

A
  • Corticosteroids are a class of steroid hormone that are produced in the adrenal cortex.
  • Glucocorticoids are anti-inflammatory (and also affect fat metabolism and bone development)
  • Corticosteroid medicines are derivatives of natural corticosteroids
  • Corticosteroids may be given systemically (oral, intramuscularly or inhaled) or topical.
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3
Q

What do mineralocorticoids control?

A

Electrolyte and water levels.

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4
Q

Describe prednisone.

A

Prednisone is a synthetic anti-inflammatory glucocorticoid steroid designed as a mimic of cortisol. It is pro-drug that only becomes active after conversion to prednisolone in the liver.

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5
Q

How does prednisone differ from cortisol?

A

The only difference between prednisone and cortisol is the presence of a carbon-carbon double bond in the A ring of prednisone. Prednisolone has a hydroxyl group on ring C in place of the carbonyl group present in prednisone.

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6
Q

Describe the mechanism of activity of prednisone.

A

Prednisone is metabolised to prednisolone in the liver. This can diffuse across cell membranes and binds with the glucocorticoid receptor (GR) which is sequestered in the cytoplasm complexed with two molecules of HSP-90.
Binding releases the HSP and the prednisolone receptor complex is translocated to the nucleus where it binds to glucocorticoid-response elements (GRE) in the promotor regions of a number of genes.

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7
Q

List and describe the side effects of corticosteroids.

A
  • Weight gain – Prednisone also causes a redistribution of body fat to undesirable places, particularly the face, back of neck and abdomen.
  • Hirsutism (excessive hairiness in unusual areas)
  • Easy bruising – due to thin skin.
  • Redistrubution on the back of the neck (Buffalo Hump) and the base of the neck
  • Glucose Intolerance – high blood sugar (steroid induced diabetes)
  • Hypertension
  • Increased susceptibility to infections
  • Osteoporosis
  • Mood swings
  • Avascular Necrosis of the Bone
  • Abdominal Striae
  • Cataracts
  • Acne
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8
Q

What are the side effects and their severity of corticosteroids based on?

A

The side effects of corticosteroids are related to the amount of steroid a patient takes and the length of time a patient remains on medication.

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9
Q

What are corticosteroids used to treat?

A
  • Autoimmune Diseases (SLE, vasculitis, rheumatoid arthritis)
  • Allergic diseases – asthma and hay fever
  • Inflammatory Diseases – (Crohns Disease)
  • Malignant Disease (Lymphoma)
  • Allograft rejection
  • Other immunological disease (ITP, glomerulonephritis)
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10
Q

Cyclophosphamide is metabolised in the cell to phosphoramide mustard and the toxic by-product Acrolein.

Phosphoramide mustard ____ 1 ____ DNA (and possibly RNA) thus interfering with DNA replication and ___2___. Effects are dependent on the phase of the cell cycle during exposure.

A
  1. Cross links

2. Transcription

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11
Q

What are the actions of the cytotoxic immunosuppressants, Cyclophosphamide and Chlormabucil?

A
  • Dose dependent lymphopenia of T (CD8>CD4) and B cells
  • Reduced B cell proliferation and antibodies (<IgG and IgM)
  • Lesser effect on T cells
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12
Q

What are cytotoxic immunosuppressants Cyclophosphamide and Chlormabucil used to treat?

A
  • Vasculitis
  • SLE
  • Glomerulonephritis
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13
Q

What are the side effects of the cytotoxic immunosuppressants Cyclophosphamide and Chlormabucil?

A
  • Bone Marrow depression
  • Alopecia
  • Haemorrhagic cystitis (caused by acrolein)
  • Sterility (males and females)
  • Secondary lymphoid neoplasms – bladder (10%), skin tumours
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14
Q

How does Methotrexate enter the cell?

What happens to Methotrexate within the cell?

A
  • Methotrexate (MTX) enters the cell through the reduced folate carrier using an endocytic pathway activated by a folate receptor.
  • MTX is then polyglutamated by the enzyme folylpolyglutamate synthase. MTX and its polyglutamates inhibit the enzyme dihydrofolate reductase, thereby blocking the conversion of dihydrofolate (FH2) to tetrahydrofolate (FH4). As tetrahydrofolate stores are depleted, thmidylate (TMP) synthesis is reduced which ultimately inhibits DNA synthesis.
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15
Q

What are the actions of the cytotoxic immunosuppressant Methotrexate?

A
  • Variable effects on lymphocyte numbers in the blood
  • Possible inhibition of cytokines
  • Inhibition of the lipo-oxygenase pathway
  • Reduction in antibody synthesis
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16
Q

What is the cytotoxic immunosuppressant Methotrexate used to treat?

A
  • GvHD in BMT
  • Adjunctive therapy with infliximab in rheumatoid arthritis
  • Psoriatic arthropathy (joint disease associated with psoriasis)
17
Q

What are the side effects of the cytotoxic immunosuppressant Methotrexate?

A
  • Mucositis, nausea and vomiting
  • Bone marrow suppression
  • Hepatic fibrosis
  • Pneumonitis
18
Q

What are the Immunomodulatory Drugs – Ciclosporin (CyA)/Tacrolimus (FK506)/Sirolimus (Rapamycin)?

Where are they derived from?

What do they do?

A
  • These three agents are macrolide antibiotics
  • They are derived from fungi

-They act specifically on T-helper cells and leave other cell types unaffected.
Target cells are inhibited but not killed

19
Q

What is the mechanism of action of Sirolimus?

A

Sirolimus (SRL) binds to FK506-binding protein (FKBP, which is the same molecule that is bound by FK506). This complex binds to the mammalian target of rapamycin (mTOR). The SRL–FKBP–mTOR complex inhibits biochemical pathways that are required for cell progression through the late G1 phase or entry into the S phase of the cell cycle. Thus, unlike cyclosporine (CsA) and FK506 (which block the production of cytokines), SRL blocks cytokine signal transduction.

20
Q

What are the uses of the Immunomodulatory Drugs – Ciclosporin (CyA)/Tacrolimus (FK506)/Sirolimus (Rapamycin)?

A
  • Used in allografts
  • SLE
  • Rheumatoid Arthritis
  • Autoimmune diseases (such as uveitis, inflammatory bowel disease)
21
Q

What are the side effects of the Immunomodulatory Drugs – Ciclosporin (CyA)/Tacrolimus (FK506)/Sirolimus (Rapamycin)?

A
  • Hypertension
  • Hirsutism
  • Nephrotoxicity
  • Hepatatoxicity
  • Lymphomas
  • Opportunistic Infections
  • Diabetes
22
Q

True or false? Mycophenolate mofetil (MMF) is a pro-drug of mycophenolic acid.

A

True

23
Q

What are the uses of the Immunomodulatory Drug – Mycophenolate Mofetil (MMF)?

A
  • Prophylaxis of allograft rejection

- Autoimmune diseases such as SLE nephritis, uveitis

24
Q

What are the side effects of the Immunomodulatory Drug – Mycophenolate Mofetil (MMF)?

A
  • Lymphopenia
  • Opportunistic infections
  • Lymphoma
  • Hepatotoxicity
25
Q

What does the immunomodulatory drug Leflunomide do?

Describe how it works.

A

Blocks T cell proliferation.

After oral administration leflunomide is converted to an active metabolite that inhibits dihydro-orotate dehydrogenase (involved in pyrimidine synthesis and required by T cells). Thus T cell proliferation is blocked.

26
Q

What are the uses of the Immunomodulatory Drug – Leflunomide?

A
  • Severe to moderate active Rheumatoid arthritis and psoriasis arthritis to reduce signs and symptoms of disease, inhibit structural damage and improve physical function.
  • Also trials in liver and renal transplants and some evidence that it has anti-viral activity (CMV)
27
Q

What are the side effects of the Immunomodulatory Drug – Leflunomide?

A
  • Severe hepatotoxicity (in combination with MTX – can be fatal)
  • Is teratogenic – women should not become pregnant for 2 years following treatment.
28
Q

Describe the history and actions of thalidomide.

A
  • Thalidomide was originally used to treat morning sickness, but was banned in the 1960s for causing serious congenital birth defects.
  • Thalidomide has subsequently been shown to have both anti-inflammatory and anti-angiogenic properties and was been licenced as a treatment for multiple myeloma.
    A series of immunomodulatory drugs — created by chemical modification of thalidomide — have been developed to overcome the original devastating side effects (this includes lenalidomide and pomalidomide).
29
Q

Describe the mechanisms of action of thalidomide and its functions.

A
  • Thalidomide and its analogues are potent inhibitors of TNFaplha production and thus inhibit inflammation. The thalidomide analogues are also very active anti-angiogenics through the inhibition of VEGF, bFGF (basic fibroblast growth factor) and IL-6.
  • Another function of thalidomide is to stimulate Th1 cell proliferation leading to increased IFN-γ and IL2 production enhancing T cell proliferation and NK activity.
  • Thalidomide also upregulates the activity of caspase 8 and inhibits apoptosis protein-2 and the pro-survival effects of IGF-1 leading to increased apoptosis in tumour cells and also decrease the formation of osteoclasts.
30
Q

All patients who undergo solid organ ___1___ require lifelong ___2___ therapy to prevent allograft rejection.

All of these drugs present toxic side effects and narrow therapeutic ranges need to be achieved for ___3___ clinical outcome.

Application of pharmacogenomics to ___4___ the dosing strategy holds promise but the clinical application is yet to be proven.

Thus blood levels of the drugs vary significantly in different individuals and ___5___ making the dosing information of little value in prediction of blood levels of the drugs.

Therefore, therapeutic drug monitoring (TDM) is essential in post-___1___ patient care.

A
  1. Transplantation
  2. Immunosuppressive
  3. Optimal
  4. Individualize
  5. Ethnicities
31
Q

Even with the use of immunosuppressants, patients have approximately a 20 to ___1___ percent risk of losing a donated organ during the first ___2___ years following transplantation, and less than ___1___ percent of patients have functioning grafts after approximately ten years. Accelerated inflammation of the graft ___3___ vessels (arteritis) is a common cause of late (chronic) organ loss.

A
  1. 50
  2. 3
  3. Blood
32
Q

Describe Antibody Based Immunosuppresion.

A
  • They are Polyclonal antibodies
  • Xenogenic antisera raised by the immunization of animals with purified human T cells or thymocytes (ATG) or rabbit anti-lymphocyte globulin (ALG) are potent immunosuppresives.
  • Although they cause a profound lymphopenia they are difficult to standarise and have significant batch to batch variation.
  • Used in acute graft rejection and GvHD
33
Q

What is Daclizumab?

How is it given?

How does it work?

A
  • Daclizumab is a humanised monoclonal antibody to the alpha subunit of the IL-2 receptor (IL2-Ralpha) (CD25) of T cells.
  • It is given in multiple doses, the first 1 hour before the transplant, and 5 further doses given at 2 weeks after the transplant.
  • The antibody prevents IL-2 binding to the receptor and thus IL-2 mediated T cell activation.
34
Q

What is Basiliximab?

How is it given?

How does it work?

What does it treat?

A
  • Basiliximab is a chimeric mouse – human monoclonal antibody to the IL2-Ralpha (CD25) of T cells.
  • It is given in two doses, the first within 2 hours of the transplant, and the second 4 days after the transplant.
  • The antibody prevents IL-2 binding to the receptor and thus IL-2 mediated T cell activation.
  • Kidney transplants.
35
Q

What is OXT3 (muromonab)?

How is it given?

How does it work?

A
  • OXT3 (muromonab) is a murine monoclonal antibody against the ε chain of the CD3 complex.
  • It is given immediately after the diagnosis of acute rejection. 5mg doses are given daily for 10-14 days.
  • In the body OKT3 acts in two phases. Firstly circulating T cells are depleted by opsonization in the liver and cytolysis. In the second phase the CD3 complex is removed producing immuno-incompetent T cells.

Clinical Immunology & Viral Pathogens (19 decks)

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