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FMS > FMS Week 10: Immunosuppressive Drugs Used in Organ Transplantation > Flashcards

FMS Week 10: Immunosuppressive Drugs Used in Organ Transplantation Flashcards

1
Q

Experiments using genetically engineered pigs to grow human organs

A
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2
Q

Attempts to regenerate organs in vivo

A
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3
Q

Crispr deleting genes of porcine pancreas

A
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4
Q

Types of Kidney Allograft Rejection

4 Listed

A
  • Hyperacute
  • Accelerated Acute
  • Acute
  • Chronic
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5
Q

Hyperacute Kidney Allograft Rejection drug treatment

2 listed

A
  • Untreatable
  • Rare because of better matching, graft preservation in transit, better induction protocols
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6
Q

Accelerated Acute Kidney Allograft Rejection Drug Treatment

A

Rarely Treatable

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7
Q

Acute Kidney Allograft Rejection Drug Treatment

9 Listed

A

Treated with

  • Cyclosporine
  • Tacrolimus
  • Sirolimus
  • Azathioprine
  • mycophenolate
  • cyclophosphamide
  • methotrexate
  • glucocorticoids
  • mAbs
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8
Q

Chronic Kidney Allograft Rejection Drug Treatment

A

Same as acute slows progression

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9
Q

Acute Antibody-Mediated Rejection

4 Listed

A
  • Antibodies against donor antigens bind to antigens expressed on endothelial cells in the graft vessel
  • The subsequent complement activation and cell adhesion result in endothelial-cell necrosis, followed by platelet deposition and coagulation
  • Mononuclear cells adhere to the endothelium of the glomeruli
  • This process is accompanied by C4d deposition in the glomeruli and peritubular capillaries and in the peritubular capillaries and in the peritubular capillaries between ghost outlines of the renal tubules
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10
Q

Chronic Antibody-Mediated Rejection Histological description

A

Antibody-Mediated rejection results in transplant glomerulopathy, with thickened glomerular capillaries and double contours accompanies by C4d in peritubular capillaries containing mononuclear cells and flocculent subendothelial material below an activated endothelial cell of the glomerular capillary

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11
Q

Immunomodulation Mechanisms

3 Listed

A
  • immunosuppression
  • specific induction of tolerance
  • immunostimulation
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12
Q

Most current drugs are?

A

Immunosuppressive

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13
Q

Immunosuppressants are used for?

3 Listed

A
  • Organ transplantation
  • Immune cell cancers
  • Autoimmune diseases
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14
Q

Immunosuppressants treatment timeline

A

Historically requiring lifelong treatment after transplantation

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15
Q

Suppression of the immune system results in Increased rates of…

3 Listed

A
  • infection
  • cancer
  • can even trigger Autoimmunity
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16
Q

Transient immunosuppressive therapy & durable chimerism

A

new techniques using donor hematopoietic stem cells and regulatory T cells with the graft suggest durable chimerism may allow transient immunotherapy

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17
Q

Guiding principles of Organ Transplantation

6 Listed

A
  • ABO compatible HLA matching
  • Combinational chemotherapy
  • Prophylactic treatment for CMV, EBV, HSV, Influenza
  • Engraftment (induction) doses > maintenance doses unless poorly functioning graft after surgery, in which case all drugs may be withdrawn and MAB treatment initiated
  • Careful investigation of dysfunctional episodes - is it due to graft rejection or drug toxicity, or infection
  • Continuous evaluation of dose:effect ratio of the administered drugs because of toxicity, notably to the kidney
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18
Q

Adrenocortical Steroids Examples

3 Listed

A
  • Prednisone
  • Prednisolone
  • others
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19
Q

Adrenocortical Steroids are used alone or

A

in combination with other immunosuppressants

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20
Q

Adrenocortical Steroids Mechanism

6 Listed

A
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21
Q

Glucocorticoid toxicities associated with chronic use

6 Listed

A
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22
Q

Glucocorticoids mechanism of Action

6 Listed

A
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23
Q

Polyclonal immunomodulatory Antibodies used as adjuncts in organ transplantation

2 Listed

A
  • Antithymocyte (ATG)
  • Antilymphocyte globulins (ALG)
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24
Q

Monoclonal immunomodulatory Antibodies used as adjuncts in organ transplantation

4 Listed

A
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25
Q

ATG AKA

A

Antithymocyte globulin (ATG)

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26
Q

ALG AKA

A

Antilymphocyte globulin (ALG)

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27
Q

ATG and ALG origin

A

e.g. from horse or sheep immunized with human T lymphocytes

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28
Q

Immunomodulatory Polyclonal Antibodies function

3 Listed

A
  • Polyclonal Antibodies to HLA I & II and to multiple CDs: 2, 3, 4, 8, 11a, 18, 25, 44, 45…
  • These Abs block immune cell function by binding to the surface and they deplete circulating lymphocytes or thymocytes by direct cytotoxicity (complement & antibody-mediated cellular cytotoxicity; CDCC, ADCC)
  • IVIG administration also decreases HLA antibodies and is effective in allograft rejection episodes
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29
Q

Immunomodulatory Polyclonal Antibodies Toxicities

3 listed

A
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30
Q

Immunomodulatory Antibodies: Monoclonal - Muromonab-CD3 (OKT-3) Function

5 Listed

A
  • Ab against CD3, the TCR complex, blocking antigen recognition and T-cell function
  • Causes internalization of TCR and increases apoptosis
  • T cell death due to complement activation
  • T cell margination and redistribution to nonlymphoid organs
  • T cells disappear from circulation in minutes returning 1 week after cessation of OKT-3
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31
Q

Muromonab-CD3 (OKT-3) is a

A

Immunomodulatory Monoclonal Antibody

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32
Q

Muromonab-CD3 (OKT-3) Toxicities

4 Listed

A
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33
Q

Immunomodulatory Antibodies: Monoclonal Anti-CD25 (IL-2R) examples

2 listed

A
  • Daclizumab
  • Basiliximab
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34
Q

Immunomodulatory Antibodies: Monoclonal: Daclizumab, Basiliximab are?

2 listed

A
  • Anti-CD25 (IL-2R) antibodies
  • humanized and chimeric (human-murine) monoclonal antibodies
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35
Q

Immunomodulatory Antibodies: Monoclonal Anti-CD25 (IL-2R) Function

4 Listed

A
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36
Q

Immunomodulatory Antibodies: Monoclonal: Anti-CD20 drug name

A

Rituximab

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37
Q

Rituximab

A

Immunomodulatory Antibodies: Monoclonal: Anti-CD20

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38
Q

Rituximab function

A
  • Anti-CD20 on B cells
39
Q

Rituximab is used in?

2 Listed

A
  • Antibody-mediated transplant rejection and post-transplant lymphoproliferative disorder (EBV reactivation)
  • also used in B-cell cancer and antibody-dependent autoimmune disease
40
Q

Immunomodulatory Antibodies: Monoclonal: Anti-CD52 drug name

A

Alemtuzumab

41
Q

Alemtuzumab is a?

A

Immunomodulatory Antibodies: Monoclonal: Anti-CD52

42
Q

Alemtuzumab function

3 listed

A
  • hMAB against CD52 on lymphocytes (T,B and NK cells, monocytes and macrophages)
  • causes extensive lympholysis due to apoptosis
  • Causes prolonged mostly T and some B cell depletion allowing drug minimalization during acute rejection
43
Q

Alemtuzumab used in?

4 Listed

A

Has shown promising results in

  • organ transplantation
  • effective in induction protocols
  • approved for CLL
  • CRS
44
Q

Abatacept and Belatacept are inhibitors of?

A

T Cell Activation

45
Q

Costimulatory blockade explanation and effect

3 Listed

A

2 signals are required for T cell activation

  • TCR and a costimulatory receptor-ligand pair
  • Blocking CD80/86 (B7) attachment to CD28 on T cells prevents activation producing energy
46
Q

Abatacept function

A

Fusion protein containing the extracellular domain of CTLA-4 and an Fc fragment that inhibits B7-CD28 bonding

47
Q

Belatacept Function

A

Second generation CTLA-4-Fc fragment blocking co-stimulation and T cell activation

48
Q

Immunosuppressants main categories

3 Listed

A
  • Calcineurin Inhibitors
  • Antiproliferative Agents
  • Antimetabolites
49
Q

Calcineurin Inhibitors examples

2 Listed

A
  • Cyclosporine (Cyclosporin A, CsA)
  • Tacrolimus (FK506)
50
Q

Antiproliferative Agents Examples

2 Listed

A
  • Sirolimus (Rapamycin)
  • Everolimus
51
Q

Antimetabolites Examples

2 Listed

A
  • Mycophenolate mofetil
  • Azathioprine
52
Q

Cyclosporine Mechanism of Action

5 Listed

A
53
Q

Cyclosporine Pharmacokinetics

3 Listed

A
54
Q

Cyclosporine Toxicities

6 Listed

A
  • Nephrotoxicity (limiting, believed due to arteriolar vasculopathy and ischemic glomerulosclerosis)
  • Neurotoxicity (tremor, limb parestesias, seizures, hallucinations)
  • Hirsutism
  • Hypertension
  • Hyperlipidemia
  • gum hyperplasia (due to inhibition of PGI2 (Prostacyclin))
55
Q

Cyclosporine Clinical Uses

5 Listed

A
  • “breakthrough drug” that permitted organ transplantation
  • Used for kidney, liver, heart, lung, bone and other tissue transplants
  • Rheumatoid arthritis
  • psoriasis
  • other autoimmune disorders
56
Q

Recurrent Gum Hyperplasia caused by?

A

Cyclosporine-associated gingival hyperplasia

57
Q

Lip Hypertrophy caused by treatment with?

A

Cyclosporine

58
Q

Lip Hypertrophy reversed with

A

Tacrolimus

59
Q

Tacrolimus (FK506) Mechanism of Action

3 Listed

A
60
Q

Tacrolimus (FK506) is metabolized by?

A

Extensively metabolized by hepatic CYP3A4 (like CsA)

61
Q

Tacrolimus limiting factor

A

Neprhotoxicity; like cyclosporine is

62
Q

Cyclosporine limiting factor

A

Nephrotoxicity; like Tacrolimus is

63
Q

Tacrolimus Toxicities

6 Listed

A
  • Nephrotoxicity
  • Neurotoxicity
  • Hypertension
  • Hyperkalemia
  • Hyperglycemia
  • Diabetes
64
Q

Glucocorticoids + Tacrolimus is…

A

Especially diabetogenic

65
Q

Tacromilus can cause _________.

A

Diabetes, and is considered diabetogenic

66
Q

Sirolimus AKA

A

Rapamycin

67
Q

Sirolimus is a

2 Listed

A
  • mTOR inhibitor
  • Antiproliferative Agent
    *
68
Q

mTOR is a what and its inhibition causes?

A
69
Q

Sirolimus prevents

A

Phsophorylation of CDK2-E and cell-cycle arrest in G1

70
Q

Sirolimus Mechanism of Action

4 Listed

A
71
Q

Sirolimus Toxicities

7 Listed

A
72
Q

Mycophenolate Mofetil class of drug

A

Antimetabolites

73
Q

Mycophenolate Mofetil is a prodrug for?

A

Mycophenolic Acid (MPA)

74
Q

MPA AKA

A

Mycophenolic Acid

75
Q

Mycophenolate Mofetil Mechanism of Action

3 Listed

A
76
Q

Mycophenolate Mofetil prevents synthesis of?

A

GTP

77
Q

MPA is ___________ before urinary excretion

A

Glucuronidated

78
Q

Mycophenolate Mofetil is used in conjunction with?

2 Listed

A
  • Glucocorticoids

and

  • Calcineurin inhibitors
79
Q

Mycophenolate Mofetil replaced the older?

A

Azathioprine

80
Q

Mycophenylate Mofetil Toxicities

3 Listed

A
  • Leukopenia
  • Diarrhea
  • Vomiting
81
Q

Azathioprine is a prodrug for

A

6-Mercaptopurine

82
Q

Azathioprine Mechanism of Action

4 Listed

A
83
Q

Azathioprine inhibits synthesis of

A
  • ATP

&

  • GTP
84
Q

Azathioprine Toxicities

3 Listed

A
85
Q

Immunosuppression increases the risk for?

3 Listed

A
  • Cancer
  • Viral infections
  • Bacterial infections
86
Q

20-40% of renal/liver transplant recipients will …

A

Develop cancer within a decade after transplantation

87
Q

Most common type of post-transplant malignancy

A

Cutaneous Squamous Cell Carcinoma

88
Q

immunosuppressants most likely to cause cancer

A

Calcineurine inhibitors (cyclosporine, tacrolimus) > mTOR inhibitors (sirolimus, everlimus)

89
Q

PTLD AKA

A

Post-transplant proliferative disorder

90
Q

PTLD occurs in ______ and has a higher incidence in those receiving ____________ and ____________ therapy.

A
  • ~1%
  • anti-thymocyte (ATG, ALG, OKT3)
  • Tacrolimus
91
Q

PTLD is

A

B cell proliferation and hyperplasia after EBV infection that can lead to B cell lymphoma

92
Q

EBV AKA

A

Epstein-Barr Virus

93
Q

Durable Chimerism Studies

A
94
Q

Immunosuppressive Agents Sites of Action

A

FMS (34 decks)

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