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Pharmacology - Winter > 8 - Immunosuppressants > Flashcards

8 - Immunosuppressants Flashcards

1
Q

Define autograft

A

Organ/tissue moving sites in the same body (self to self)

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2
Q

Define allograft

A

Organ/tissue moving from one human to another

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3
Q

We want to make organ/tissue transplants as _____-like as possible to prevent rejection

A

Autograft-like

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4
Q

Define xenograft

A

Organ/tissue moving from one species to another

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5
Q

What are the 3 types of organ/tissue rejection?

A
  • Hyperacute = minutes
  • Acute = 7-21 days
  • Chronic = 3 months
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6
Q

What do anti-rejection drugs target?

A
  • T-cell and B-cell activation/clonal expansion
  • Cytokine production, or
  • Antibody action
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7
Q

What is a big contributor to the success of organ transplantation?

A

Effective immunosuppressive agents

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8
Q

How are antibodies formed?

A
  • Antigen binds to antigen receptor, activating a B cell; cytokines are released from helper T cells
  • B cell undergoes proliferation to form 2 clones of B cells
  • Clones of B cells undergo proliferation and differentiation to form plasma cells (antibody secreting cells) and memory cells (dormant cells)
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9
Q

What is the induction phase of the immune response?

A

Antigen recognition on B cell and proliferation of B cell

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10
Q

Which drugs target the induction phase of the immune response?

A
  • Cyclosporine and tacrolimus inhibit interleukin-2 production
  • Glucocorticoids inhibit cytokine gene expression
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11
Q

What is the function of interleukin-2 for the immune response?

A

Needed for helper T cells to be activated

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12
Q

Indication of cyclosporine

A
  • Tx of organ transplantation (kidney, heart, bone marrow)

- Low doses used in autoimmune diseases (ex: RA)

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13
Q

What is the MOA of cyclosporine?

A
  • Antigen-MHC 2 complex bind to Th-2 cell receptor, increasing intracellular Ca2+
  • Ca2+/calmodulin complex stimulates calcineurin => increased activation of transcription factor => increased IL-2 gene transcription
  • Cyclosporine binds to cytosolic protein cyclophilin; this complex inhibits calcineurin/NF-AT activation and blocks IL-2 gene transcription
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14
Q

What are the functions of cyclosporine?

A
  • Decrease activation of T cells (inhibits IL-2 release and decreases expression of IL-2 receptors)
  • Reduces function of effector T cells that mediate cell-mediated responses
  • Reduces T cell-dependent B cell response
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15
Q

What are side effects of cyclosporine and tacrolimus?

A
  • Nephrotoxicity (so must monitor kidneys)
  • Hypertension
  • Increased risk of infection
  • Liver dysfunction
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16
Q

What drugs do cyclosporine interact w/?

A
  • Drugs that inhibit CsA metabolism (Ca channel blockers, antifungals, antibacterials, grapefruit juice)
  • Drugs that induce CsA metabolism (anticonvulsants, antituberculosis agents)
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17
Q

What is the MOA of tacrolimus?

A
  • Similar to cyclosporine
  • Binds to immunophilin FK binding protein (FKBP) which inhibits calcineurin phosphatase => decreased activation of transcription factors => decreased IL-2 gene transcription
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18
Q

What is the effector phase of the immune response?

A

Production of clones of B-cells, differentiation of clones into T cells or antibodies, and joining w/ antigens at site of tissue injury

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19
Q

Which drugs act on the effector phase of the immune response?

A
  • Sirolimus (inhibits interleukin 2 mediated gene activation)
  • Myclophenolate mofetil and azathioprine (inhibit purine synthesis)
  • Cyclophosphamide (alkylates cytotoxic agents)
  • Glucocorticoids (suppress immune response)
  • Polyclonal and monoclonal antibodies (immunosuppressive)
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20
Q

What is the MOA of sirolimus?

A
  • Binds to intracellular immunophilins
  • Interferes w/ IL-2 signal transduction pathway in activated T cells
  • Result = decreased clonal proliferation of T and B cells
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21
Q

What is the MOA of mycophenolate mofetil?

A

Potent inhibitor of inosine 5’-monophosphate dehydrogenase (crucial enzyme in purine synthesis)

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22
Q

What can impair the absorption of mycophenolate mofetil?

A

Magnesium and aluminum

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23
Q

What is the indication of mycophenolate mofetil?

A

Transplant recipients w/ cyclosporine and steroids

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24
Q

What is the MOA of azathioprine?

A
  • Interferes w/ purine synthesis (inhibit HGPRT enzyme, which catalyzes conversion of purine base to purine ribosyl monophosphate)
  • Inhibits clonal T and B cell proliferation of immune response
  • Inhibits both cell mediated and antibody mediated immune reactions
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25
Q

What are the indications of azathioprine?

A
  • IV loading dose on day of transplantation
  • Oral dosing for maintenance
  • Used in combination w/ other immunosuppressant drugs
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26
Q

What is the major side effect of azathioprine?

A

Bone marrow depression

27
Q

What is the MOA of cyclophosphamide?

A

Alkyl groups cross-react w/ 2 DNA nucleophilic sites to inhibit DNA replication and cause subsequent cell death (apoptosis)

28
Q

What are the indications of cyclophosphamide?

A

Tx of lupus and RA

29
Q

What are side effects of cyclophosphamide?

A

Bone marrow depression and GI disturbance

30
Q

Which glucocorticoids are used as immunosuppressants?

A
  • Prednisone
  • Methylprednisone
  • Dexamethasone
31
Q

What do high doses of glucocorticoids cause?

A

Induce lymphocyte migration to extravascular space and subsequently reduce lymphocyte proliferation

32
Q

Glucocorticoids affect more ___ cells than ___ cells

A

More T cells than B cells

33
Q

What is the MOA of glucocorticoids?

A
  • Suppress induction and effector phases of immune response
  • Inhibit macrophage activation and release of IL-1 beta
  • Decrease clonal expansion of T and B cells and IL-2 secreting T cells
  • Decrease production and action of cytokines
  • Decrease generation of IgG
34
Q

What are the clinical uses of glucocorticoids?

A
  • Anti-inflammatory and immunosuppressive therapy
  • Neoplastic diseases (Hodgkin’s disease, acute lymphocytic leukemia)
  • Replacement therapy
35
Q

What are side effects of glucocorticoids?

A
  • Insomnia and mood changes
  • Increased appetite and weight gain
  • Suppressed response to injury or infection
  • Metabolic effects
36
Q

What are immunosuppressive antibodies?

A

Antibodies against human lymphocytes or their surface receptors that have significant immunosuppressant actions

37
Q

What are polyclonal antibodies?

A
  • Anti-lymphocyte immunoglobulin (inhibit T cell lysis)

- Bind to proteins on surface of lymphocytes triggering complement response => lysis of lymphocytes

38
Q

What are adverse effects of polyclonal antibodies?

A

Newly synthesized antibodies against these polyclonal antibodies could produce anaphylactic reactions

39
Q

What are monoclonal antibodies?

A

Antibodies against IL-2 receptors (prevent T and B cell activation and proliferation)

40
Q

What are the targets of monoclonal antibodies?

A
  • CD3 proteins w/ antigen receptors
  • CD4 co-receptors
  • IL-2 receptors
41
Q

What drugs are given to prevent an acute rejection?

A

High dose glucocorticoids, purine synthesis inhibitors and immunosuppressive antibodies 1-2 weeks prior to transplant

42
Q

Which drugs are given to prevent a chronic rejection?

A

Low dose triple drug therapy (calcineurin inhibitor, purine synthesis inhibitor, and glucocorticoid)

43
Q

What drugs are used for a breakthrough episode in chronic rejection?

A
  • Cyclophosphamide
  • Immunosuppressive antibodies (polyclonal and monoclonal)
  • Anti-TNF therapy
44
Q

What is the purpose of primary and peripheral tolerance of the immune system?

A

Protect itself against autoreactive B and T cells

45
Q

Where does central tolerance occur and what is it?

A
  • Occurs in lymphoid organs
  • Clonal deletion of immature lymphocytes in bone marrow (B cells) and thymus (T cells) that recognize self-antigens w/ high affinity
46
Q

Where does peripheral tolerance occur and what is it?

A
  • Occurs beyond lymphoid organs

- Kills or inactivates mature autoreactive lymphocytes

47
Q

What happens when self-tolerance mechanisms fail?

A

Adaptive immune system responds as it would to non-self antigens and mounts an immune response

48
Q

What can be caused by the body’s inability to eliminate self-antigen?

A

Sustained response that leads to chronic inflammation

49
Q

Which drugs are anti-IL therapeutics?

A
  • Anakinra
  • Canakinumab
  • Tocilizumab
50
Q

Which drugs are anti-TNF therapeutics?

A
  • Entanercept (only soluble receptor TNF antagonist)
  • Infliximab
  • Adalimumab
  • Certolizumab
  • Golimumab
51
Q

Why are anti-TND and anti-IL effective DMARDs (disease-modifying antirheumatic drugs)?

A
  • Released w/in joint during chronic inflammatory phase

- Early participants in inflammatory cascade

52
Q

What occur in the 3 phases of rheumatoid arthritis?

A
  • Initiation phase = inflammation w/in joint
  • Amplification phase = T cell activation
  • Chronic inflammatory phase = tissue injury due to destruction of bone and remodeling of joint
53
Q

Which drugs are used in rheumatoid arthritis therapy?

A
  • NSAIDs
  • Glucocorticoids
  • Disease-modifying antirheumatic drugs (DMARDs)
54
Q

Which drugs are DMARDs?

A
  • Methotrexate
  • Sulfasalazine
  • Leflunomide
  • Anti-TNF therapies
  • Anti-IL therapies
55
Q

What do autoreactive T helper 1 cells cause?

A

Release interferon and interleukin to activate macrophages that secrete additional cytokines to cause local inflammation

56
Q

What do autoreactive cytotoxic T cells cause?

A

Extensive tissue damage

57
Q

What affect do inappropriate T cell responses have on autoreactive B cells?

A

Help autoreactive B cells initiate polyclonal activation and generation of harmful auto-antibodies

58
Q

What do auto-antibodies do?

A
  • Activate complement system to cause inflammation
  • Bind receptors to block hormone and NT signals, or
  • React w/ antigens in blood
59
Q

What is the purpose of clonal deletion in central tolerance?

A

To safeguard against autoreactive lymphocytes

60
Q

What does viral infection of a tissue cause?

A

Activation of non-virus-specific T cells

61
Q

What is molecular mimicry?

A

Microbial antigens shape epitopes similar to human self-proteins and induce an inflammatory response against the self-antigen

62
Q

What are DAMPs? What can they trigger?

A
  • Damage-associated molecular patterns
  • Molecules released from stressed or injured cells that act as danger signals to alert the immune system
  • May trigger autoimmunity
63
Q

What can nucleic acids released from dying cells cause?

A

Can stimulate toll-like receptors (TLRs) on B cells and promote auto-antibody generation

Pharmacology - Winter (18 decks)

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