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Genetics; Protection II > CN2: Organ Transplantation > Flashcards

CN2: Organ Transplantation Flashcards

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1
Q

What is an example of autograft?

A

Skin graft from one part of the body to another

No transplant rejection

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2
Q

What is the tissue transplant from the same species?

A

Homograft

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3
Q

What is the tissue transplant from different species?

A

Xenograft

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4
Q

What are the organs that can be transplanted to humans?

A
  1. Skin appendages
  2. Bone
  3. BM
  4. Liver
  5. Kidney
  6. Heart
  7. Lungs
  8. Pancreas
  9. Spleen
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5
Q

What is to determine probable compatibility of donor and recipient?

A

Mendelian mode of inheriting MHC Ag

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6
Q

Each individual has how many MHC Ag that is inherited from the mother and one from the father?

A

Diploid (has 2 sets)

example: mother with sets AB and father has sets CD, their offspring may have AC, AD, BC, or BD; therefore probabilities are:
- 25% having the same 2 sets
- 50% having only one set

the same implications:
- there’s a 25% probability of finding the most compatible donor among ones’ own sibling
- the monozygote twin is the best possible donor
- there’s a 50% chance that 2 siblings share one set of MHC Ags
- a parent and child share only one set of MHC Ags

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7
Q

Define transplant rejection

A

The immunological response to incompatibility in a transplanted organ.

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8
Q

How much is the probability of finding the most compatible donor among ones’ own siblings?

A

25%

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9
Q

What is the best possible donor?

A

Monozygote twin

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10
Q

How much is the chance that 2 siblings share one set of MHC Ag?

A

50%

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11
Q

How many MHC Ag does a parent and child share?

A

One set

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12
Q

What are the different mechanisms of rejection?

A
  1. T cell-mediated reactions
    a. Direct pathway
    b. Indirect
  2. Ab mediated
    a. Hyperacute rejection
    b. Acute Ab-mediated rejection
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13
Q

MHC Ag on cell-surface of APC of donor organ:

A

Direct pathway

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14
Q

Class II Ag recognized by CD4+ T cell to:

direct pathway

A

Cytokines produced to induct macrophages and lymphocytes as effector cells

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15
Q

Class I Ag recognized by CD8+ T cell to:

direct pathway

A

Activate cytotoxic T cells as killer cells

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16
Q

Recipient T cells recognize alloAg from donor only when presented by the host’s own antigen-presenting cell (APC)

A

Indirect pathway

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17
Q

What involves preformed Ab (in previously sensitized individual)?

A

Hyperacute rejection

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18
Q
  • occurs within minutes of transplantation
  • Ag-Ab rxn at lvl of vascular endothelium
A

Hyperacute rejection

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19
Q

Type of rejection in a recipient not previously sensitized cause of injury:

A

Acute Ab-mediated rejection

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20
Q
  • complement-dependent cytotoxicity
  • Ab-dependent cell-mediated cytolysis
  • deposition of Ag-Ab complexes graft vasculature is initial target, an immunologic vasculitis
A

Acute Ab-mediated rejection

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21
Q

Rejection reactions are classified as:

A

Hyperacute, acute, and chronic

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22
Q

What rejection occurs within minutes or hours after transplantation and can be recognized by the surgeon just after the graft vasculature is anastomosed to the recipient’s?

A

Hyperacute rejection

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23
Q

In contrast to a nonrejecting kidney graft, which rapidly regains a normal pink coloration and normal tissue turgor and promptly excretes urine;

a hyper-acutely rejecting kidney becomes:

A

Cyanotic
Mottled
Flaccid
May excrete a mere few dps of bloody urine

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24
Q

Immunoglobulin and complement are deposited in the vessel wall, and electron microscopy discloses early endothelial injury together with fibrin-platelet thrombi.

A

Early lesions point to Ag-Ab rxn at the level of vascular endothelium

subsequently, these changes become diffuse and intense, the glomeruli undergo thrombotic occlusion of the capillaries, and fibrinoid necrosis occurs in arterial walls. the kidney cortex then undergoes outright infarction (necrosis), and such nonfxning kidneys have to be removed.

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25
Q

As the changes become diffuse and intense, the glomeruli undergo what?

A

Thrombotic occlusion of capillaries

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26
Q

Where does fibrinoid necrosis occur?

A

Arterial walls

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27
Q

What may occur within days of transplantation in the untreated recipient or may appear suddenly months or even years later, after immunosuppression has been employed and terminated?

A

Acute rejection

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28
Q

What is a combined process in wc both cellular and humoral tissue injuries contribute?

In any one patient, one or the other mechanism may predominate.

A

Acute graft rejection

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29
Q

Histologically, what is humoral rejection associated with?

A

Vasculitis

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30
Q

Histologically, what is cellular rejection marked by?

A

Interstitial mononuclear cell infiltrate

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31
Q

What is most commonly seen within the initial months after transplantation and is heralded by an elevation of serum creatinine lvls followed by clinical signs of renal failure?

A

Acute cellular rejection

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32
Q

Histological appearance of acute cellular rejection:

A
  • extensive interstitial mononuclear infiltration
  • edema
  • mild interstitial hemorrhage
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33
Q

What staining reveals CD4 & 8, and these cells express markers of activated T cells s/a alpha chain of the IL-2 receptor?

A

Immunoperoxides

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34
Q

Glomerular and peritubular capillaries contain large numbers of mononuclear cells that may invade the tubules causing what?

A

Focal tubular damage

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35
Q

CD8 might also injure vascular endothelial cells causing what?

A

Endothelitis

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36
Q

What is important bcs in the absence of an accompanying arteritis, px promptly respond to immunosuppressive therapy?

A

Recognition of cellular rejection

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37
Q

What is a widely used immunosuppressive drug which is nephrotoxic hence histologic changes resulting from it may be superimposed?

A

Cyclosporine

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38
Q

What is mediated primarily by anti-donor Ab, hence is manifested mainly by damage to the BV?

A

Acute humoral rejection (rejection vasculitis)

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39
Q

Acute humoral rejection (rejection vasculitis) may take the form of necrotizing vasculitis with:

A
  • Endothelial cell necrosis
  • Neutrophilic infiltration
  • Deposition of Ig
  • Complement
  • Fibrin
  • Thrombosis

lesions are associated with extensive necrosis of the renal parenchyma

in many cases, the vasculitis is less acute and is characterized by marked thickening of the intima by proliferating fibroblasts, myocytes, and foamy macrophages

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40
Q

What may happen when there is the narrowing of arterioles?

A

May cause infarction or renal cortical atrophy

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41
Q

What are c/b cytokines that cause growth of vascular smooth muscles?

A

Proliferative vascular lesions mimic arteriosclerotic thickening

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42
Q

What is an important cause of graft failure?

since acute rejection has been ctrlled by immunosuppressives

A

Chronic rejection

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43
Q

Px with chronic rejection present clinically w a progressive rise in what?

A

Serum creatinine over a pd of 4-6 mos

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44
Q

What is dominated by vascular changes, interstitial fibrosis, and tubular atrophy w loss of renal parenchyma?

A

Chronic rejection

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45
Q

What is consist of dense, obliterative intimal fibrosis, principally in the cortical arteries?

A

Vascular changes

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46
Q

The vascular lesions result in what?

A
  • renal ischemia manifested by glomerular loss
  • interstitial fibrosis and tubular atrophy
  • shrinkage of the renal parenchyma
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47
Q

The glomeruli may show duplication of basement membranes; this appearance is sometimes called what?

A

Chronic transplant glomerulopathy

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48
Q

Chronically rejecting kidneys usually have mononuclear cell infiltrate containing large numbers of what?

A
  • Plasma cells
  • Numerous eosinophils
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49
Q

What are the major targets of transplant rejection?

A

HLA Antigens

minimizing the HLA disparity between the donor and the recipient would be expected to improve graft survival

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50
Q

HLA and transplants examples:

A
  • Related donor kidney transplants, a beneficial effect of matching for HLA class I is observed
  • Cadaver renal transplants, matching for HLA class I Ags (HLA-A and HLA-B) has at best a modest effect on graft acceptance
  • Additional matching for class II Ag (HLA-DR) results in a definite improvement in graft survival

However, even HLA-matched unrelated donors are likely to difer from the host at one or more minor histocompatibility Ag. These antigens are formed by peptides derived from polymorphic proteins other than those encoded in the HLA complex. They evoke a weak or slower rejection reaction that, nevertheless, necessitateds the use of immunosuppression.

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51
Q

Except in the case of identical twins, who are obviously matched for all possible histocompatibility Ags, what is a practical necessity in all other donor-recipient combinations?

A

Immunosuppresive Therapy

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52
Q

What is the mainstay of immunosuppression?

A

Cyclosporine

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53
Q

What works by blocking activation of a transcription factor called nuclear factor of activated T cells, which is required for transcription of cytokine gene (IL-2)?

A

Cyclosporine

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54
Q

What is used to treat rejections which inhibits leukocyte development from BM precursors?

A

Azathioprine

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55
Q

What is used to treat rejections which can block inflammation?

A

Steroids

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56
Q

What are used to treat rejections which can inhibit lymphocyte proliferation?

A

Rapamycin
Mycophenolate mofetil

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57
Q

What blocks the activation and may opsonize and help to eliminate the cells?

A

Monoclonal anti-T-cell Ab

e.g., monoclonal anti-CD3 and Ab against IL-2 receptor a chain, which block T-cell activation and may opsonize and help to eliminate the cells

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58
Q

What are used to dampen the immune response in organ transplantation and autoimmune dse?

A

Immunosuppressive drugs

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59
Q

In transplantation, the major classes of drugs used today are:

A

1) glucocorticoids
2) calcineurin inhibitors
3) anti proliferative/anti metabolic agents

These drugs have met with a high degree of clinical success in treating conditions such as acute immune rejection of organ transplants and severe autoimmune diseases. However, such therapies require lifelong use and nonspecifically suppress the entire immune system, exposing px to considerably higher risks of infection and cancer.

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60
Q

What can be nephrotoxic and diabetogenic?

A

Calcineurin inhibitors and steroids

these are of limited usefulness in a variety of clinical setting

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61
Q

What are important adjunt therapies and provide a unique opportunity to selectively target specific immune-reactive cells and thus promote more specific tx?

A

Monoclonal and polyclonal antibody preparations directed at reactive T cells

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62
Q

What are being used to target growth factor pathways, substantially limiting clonal expansion and thus promoting tolerance?

A

Sirolimus and anti-CD25 (IL-2 receptor) Ab (basiliximab, daclizumab)

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63
Q

What are the 5 general principles of organ transplant therapy?

A

1) careful px prep and selection of best available ABO-compatible HLA match for organ donation

2) a multititered approach to immunosuppressive drug therapy (several agents are used simultaneously, each of which is directed at a different molecular target within the allograft response. Synergistic effects are obtained through application of the various agents at a relatively low doses, thereby limiting specific toxicities while maximizing the immunosuppressive effect)

3) greater immunosuppression

4) careful investigation of each episode of transplant dysfxn (eval for rejection, drug toxicity, infxn; they can co-exist)

5) redxn or withdrawal of a therapeutic agent when toxicity exceeds its benefit

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64
Q

To gain early engraftment and/or to treat established rejection than maintain immunosuppression in the long term:

therefore, intensive induction and lower-dose maintenance drug protocols are employed

A

Greater immunosuppression

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65
Q

Response elements in DNA (regulate gene transcription)

A

Glucocorticoids

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66
Q

T-cell receptor complex (blocks Ag recognition)

A

Muromonab-CD3

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67
Q

Calcineurin (inhibits phosphatase activity)

A

Cyclosporine and Tacrolimus

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68
Q

DNA (false nucleotide incorporation)

A

Azathioprine

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69
Q

Inosine monophosphate dehydrogenase (inhibits activity)

A

Mycophenolate mofetil

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70
Q

IL-2 receptor (block IL-2-mediated T cell activation)

A

Daclizumab, Basiliximab

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71
Q

Protein kinase involved in cell-cycle progression (mTOR) (inhibits activity)

A

Sirolimus

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72
Q

What are used as induction therapy in the immediate post transplantation period?

A
  • Muromonab-CD3
  • Anti-CD25 monoclonal Ab
  • Polyclonal anti-lymophocyte Ab
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73
Q

These tx enables initial engraftment without the use of high doses of nephrotoxic calcineurin inhibitors:

A

Muromonab-CD3
Anti-CD25 monoclonal Ab
Polyclonal antilymophocyte Ab

such protocols reduce the incidence of early rejection and appear to be particularly beneficial for patients, pediatric recipients, or African Americans

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74
Q

What are directed at a discrete site in T cell activation?

A
  • Calcineurin inhibitor
  • Steroids
  • Mycophenolate mofetil

  • typical therapy
  • also basic immunosuppressive protocol used in most transplant center involves the use of multiple drugs simultaneously
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75
Q

What is a purine metabolism inhibitor?

A

Mycophenolate mofetil

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76
Q

What are effective in preventing acute cellular rejection but not as effective in blocking T cells that already are activated, and are not very effective against established, acute rejection or for total prevention of chronic rejection?

A

Low doses of prednisone, calcineurin inhibitors, purine-metabolism inhibitors, or sirolimus

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77
Q

Agents directed against activated T cells

A
  • Glucocorticoids in high doses (pulse therapy)
  • Polyclonal antilymophocyte Ab
  • Muromonab-CD3
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78
Q

Steroids lyse and induce the redistribution of lymphocytes = rapid, transient decrease in peripheral blood lymphocyte cts

For long term effects to occur: they bind to receptors inside cells, then receptors OR glucocorticoid-induced CHON bind to DNA = transcription

additonally, glucocorticoid-receptor complexes increase IkB expression, thereby curtailing activation of NFkB, which results in increased apoptosis of activated cells.

Of central importance is the downregulation of important proinflammatory cytokines s/a IL-1 and IL-6.

T cells are inhibited from making IL-2 and proliferating. The activation of cytotoxic T lymphocytes is inhibited. Netro and monocytes display poor chemotaxis and decreased lysosomal enx release.

Therefore, glucocorticoids have broad antiinflammatory effects on cellular immunity. In contrast, they have relatively little effect on humoral immunity.

A

Adrenocortical steroids MOA

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79
Q

Central impt: down-regulation of proinflammatory cytokines (IL-6, IL-1)

A

Adrenocortical steroids

80
Q

What are commonly used in combination with other immunosuppressive agents both prevent and treat transplant rejection?

A

Glucocorticoids

81
Q

What are used to reverse acute transplant rejection and acute exacerbations of selected autoimmune disorders?

A

High doses of IV methylprednisone sodium succinate (SOLUMEDROL, A-METHAPRED) (pulses)

82
Q

What are efficacious for tx of GVHD in BM transplantation?

A

Glucocorticoids

83
Q

What are routinely used to treat RA, SLE, systemic dermatomyositis, psoriasis, asthma, allergic dis, inflammatory bowel dse, inflammatory ophthalmic dses, autoimmune hema dis, and acute exacerbations of multiple sclerosis?

A

Glucocorticoids

84
Q

Glucocorticoids limit allergic rxns that occur w other immunosuppressive agents and are used in transplant recipients to block first-dose cytokine storm by tx with:

A

Muromonab-CD3

85
Q

Extensive use of steroids has resulted in disabling and life-threatening adverse effects s/a:

A
  • growth retardation
  • avascular necrosis of bone
  • osteopenia
  • inc risk of infxn
  • poor wound healing
  • cataracts
  • hyperglycemia
  • HPN
86
Q

What target intracellular signaling pathways induced as a consequence of T cell receptor activation?

A

Calcineurin inhibitors, cyclosporine, tacrolimus

most effective immunosuppressive drugs in routine clinical use

87
Q

Most effective immunosuppressive drugs in routine clinical use:

A

Calcineurin inhibitors, cyclosporine, tacrolimus

inhibit normal T cell signal transduction

88
Q

Cyclosporine and tacrolimus do not act per se as immunosuppressive agents. Instead, they “gain fxn” after binding to cyclophilin or FKBP-12, resulting to subsequent interaction w calcineurin to:

A

Block activity of this phosphatase

89
Q

What is required for movement of a component of the nuclear factor of activated T lymphocytes (NFAT) into nucleus?

A

Calcineurin-catalyzed dephosphorylation

90
Q

What is required for induction of a number of cytokine genes including that for IL-2, a prototypic T cell growth and differentiation factor?

A

NFAT (nuclear factor of activated T lymphocytes)

91
Q
  • cyclic polypeptide 11 AA
  • produced as metabolite of fungus sp Beauveria nivea
  • lipophilic and highly hydrophobic, so must be solubilized for clinical administration

of note: all amide nitrogens are either hydrogen bonded or methylated, the single D-amino acid is at position 8, the methyl amide between residues 9 and 10 is in the cis configuration, and all other methyl moieties are in the trans form.

A

Cyclosporine (cyclosporine A)

92
Q
  • Cyclosporine inhibits Ag-triggered signal transduction in T lymphocytes, blunting expression of many lymphokines (IL-2 and anti-apoptotic proteins)
  • Cyclosporine forms a complex w cyclophilin (complex binds to calcineurin, inhibiting Ca2+-stimulated dephosphorylation of cytosolic component of NFAT. NFAT translocates to the nucleus where it complexes with nuclear components required for complete T-cell activation, including transactivation of IL-2 and other lymphokine genes.
  • Calcineurin enzymatic activity is inhibited frollowing physical interaction w the cyclosporine/cyclophilin complex.
  • Results: blockade of NFAT dephosphorylation; thus, the cytoplasmic component of NFAT doesn’t enter the nucleus, gene transcription isn’t activated, and T lympho fail to respond to specific Agnic stimulation.

Cyclosporine supress some humoral immunity but most effective against T cell-dependent immune mechanisms s/a those underlying transplant rejection and some forms of autoimmunity.

A

Cyclosporine MOA

Cyclosporine also increases expression of transforming growth factor B (TGF-B), a potent inhibitor of IL-stimulated T-cell proliferation and generation of cytotoxic T lymphocytes (CTL)

93
Q

What is a cytoplasmic receptor protein present in target cells?

A

Cyclophilin

94
Q

This complex binds to calcineurin, inhibiting Ca 2+ stimulated dephosphorylation of the cytosolic component of NFAT:

A

Cyclosporine-cyclophilin complex

95
Q

Cyclosporine increases expression of what?

A

Transforming growth factor B

96
Q

What is a potent inhibitor of IL-2 stimulated T cell proliferation and generation of cytotoxic T lymphocytes?

A

Transforming growth factor B

97
Q

Disposition and Pharmakokinetics of Cyclosporine

A
  • IV or orally
  • IV (SANDIMMUNE) as ethanol -polyxyethylated castor oil vehicle –> diluted in 0.9% NaCl or 5% dextrose
  • Oral - soft gel capsule 20-50% bioavailability
  • NEORAL - more uniform & slightly inc bioavailability
98
Q

Terminal half life of cyclosporine

A

5-18 hrs

99
Q

After IV infusion, clearance is approx what in adult recipients of renal transplants?

A

5-7 mL/min per kg

100
Q

Following oral administration of cyclosporine (as NEORAL), the time to peak blood conc is:

A

1.5 to 2 hrs

101
Q

How many % of cyclosporine is excreted unchanged in urine?

A

0.1%

102
Q

Cyclosporine is extensively metabolized in the liver by what enz system to a lesser degree by GI tract and kidneys?

A

Cytochrome-P459 3A (CYP3A)

103
Q

Where are Cyclosporine and its metabolites excreted?

clinical indications for cyclo: kidney, heart, liver, other organ transplantation; RA and psoriasis

A
  • Principally: thru bile into the feces
  • Approx. 6% being excreted in the urine
  • Also in human milk

in hepatic dysfxn, dosage adjustments are required

no necessary adjustments for dialysis or renal failure px

104
Q

What is generally recognized as the agent that ushered in the modern era of organ transplantation, increasing the rates of early engraftment, extending graft survival for kidneys, and making cardiac and liver translpant possible?

A

Cyclosporine

usually used in combination w other agents, esp glucocorticoids and either azathrioprine or mycophenolate mofetil, and most recently sirolimus.

105
Q

Dosage is guided by:

A
  • signs of rejection (too low a dose)
  • renal or other toxicity (too high a dose)
  • close monitoring of blood lvls

  • initial dose generally is not given pretransplant bcs of concern about neurotoxicity
  • especially for renal px: therapeutic algorithms have been developed to delay cyclosporine introdxn until a threshold renal fxn has been attained
106
Q

In rheumatoid arthritis, cyclosporine is used in cases of severe dse that have NOT responded to:

A

Methotrexate

107
Q

In psoriasis, ________ is indicated for the tx of adult nonimmunocompromised px w severe and disabling dse who have failed other systemic therapies.

A

Cyclosporine

because of its mechanism of action, there is a theoretical basis for the use of cyclosporine in a variety of other T-cell mediated dses

  • reported to be effective in Behcet’s acute ocular syndrome, endogenous uveitis, atopic dermatitis, inflammatory bowel dse, and nephrotic syndrome when standard therapies have failed.
108
Q

What are the principal adverse reactions to cyclosporine therapy?

A 
Renal dysfxn
Tremor
Hirtutism
HPN
Hyperlipidemia
Gum hyperplasia

Nephrotoxicity is limiting and occurs in the majority of px treated.

It is a major indication for cessation or modification of therapy.

Hypertension may occur in approx 50% of renal transplant and almost all cardiac transplant px.

109
Q

Combined use of calcineurin inhibitors and glucocorticoids is what?

A

Diabetogenic

with diabetes being more frequent in patients treated with tacrolimus than in those receiving cyclosporine

110
Q

Inhibiting CYP3A can what?

A
  • Decrease cyclosporine metabolism
  • Increase blood conc

  • Ca channel blockers (verapamil, nicardipine)
  • Antifungal agents (fluconazole, ketoconazole)
  • Antibiotics (erythromycin)
  • Glucocorticoids (methylprednisolone)
  • HIV-protease inhibitors (indinavir)
  • other drugs (allopurinol, metoclopramide)
111
Q

Inhibit enz can decrease cyclosporine metabolism and increase bld conc:

A
  • Ca channel blockers (verapamil, nicardipine)
  • antifungal (fluconazole, ketoconazole)
  • antibiotics (erythromycin)
  • glucocorticoids (methylprednisone)
  • HIV-protease inhibitors (indinavir)
  • allopurinol, metoclopramide
112
Q

What can block the CYP3A system and increase cyclosporine blood conc and thus should be avoided by px receiving the drug?

A

Grapefruit and grapefruit juice

113
Q

Drugs that induce CYP3A activity can what?

A

Increase cyclosporine metabolism and decrease blood concentrations

  • antibiotics (nafcillin and rifampin)
  • anticonvulsants (phenobarbital anf phenytoin)
  • other drugs (octreotide and ticlopidine)
114
Q

What aggravates cyclosporine-induced renal dysfxn?

A

Sirolimus

interactions between cyclosporine and sirolimus have led to the recommendation that administration of the 2 drugs be separted by time

115
Q

What increases sirolimus-induced hyperlipidemia and myelosuppression?

A

Cyclosporine

other cyclosporine-drug interactions include additive nephrotoxicity when coadministered w NSAIDs and other drugs that cause renal dysfxn; and reduced clearance of other drugs, including prednisolone, digoxin, and lovastatin

116
Q

What is a macrolide antibiotic produced by Streptomyces tsukabaensis?

A

Tacrolimus

117
Q

MOA: inhibits T cell activation by inhibiting calcineurin

  • binds to an intracellular protein, FK506-binding protein-12 (FKBP-12)
A

Tacrolimus

118
Q

What binds to an intracellular protein, FK506-binding protein-12 (FKBP-12), an immunophilin structurally related to cyclophilin?

A

Tacrolimus

A complex tacrolimus-FKBP-12, Ca, calmodulin, and calcineurin then forms, and calcineurin phosphatase activity is inhibited.

The inhibition of phosphatase activity prevents dephosphorylation and nuclear translocation of NFAT and leads to inhibition of T-cell activation. Although, the intracellular receptors differ, cyclosporine and tacrolimus appear to share a single common pathway of immunosuppression.

119
Q

Tacrolimus is available for oral administration as capsules and a sterile solution for injection?

A

capsules: 0.5, 1 and 5mg
IV: 5mg/dL

Immunosuppressive activity resides primarily in the parent drug because of intersubject variability in pharmacokinetics, individualization of dosing is required for optimal therapy.

120
Q

What is the most appropriate sampling compartment to describe tacrolimus pharmacokinetics?

A

Whole blood

121
Q
  • GI absorption is incomplete and variable
  • food decreases both rate and extent of absorption
  • plasma protein binding of tacrolimus is 75-99%, involving primarily albumin and a1-acid glycoprotein

Tacrolimus half-life is:

A

12 hours

122
Q

Tacrolimus is extensively metabolized in the liver by what?

A

CYP3A

The bulk of excretion of parent drug and metabolites is in the FECES.
Less than 1% of administered tacrolimus is excreted unchanged in the urine.

123
Q

What is indicated fot the prophylaxis of solid-organ allograft rejection in a manner similar to cyclosporine and as rescue therapy in px w rejection episodes despite “therapeutic” lvls of cyclosporine?

A

Tacrolimus

recommended dose:
- injection: 0.03-0.05mg/kg per day as a continuous infusion

recommended initial oral doses:
- 0.2mg/kg per day for adult kidney transplant px
- 0.1-0.15mg/kg per day for pediatric liver transplant px in 2 divided doses 12 hrs apart

these dosages are intended to acheive typical blood trough lvls in the 5-20mg/mL range; pedia px require higher doses than adults

124
Q

Toxicity of Tacrolimus:

A 
Nephrotoxic
Neurotoxic (tremor, headache, motor disturbances, seizures)
GI complaints
HPN
Hyperkalemia
Hyperglycemia
Diabetes

Risk: secondary tumors and opportunistic infxn

as with cyclosporine, nephrotoxicity is limiting

125
Q

Tacrolimus has a negative effect on

A

Pancreatic islet beta cell

both glucose intolerance and diabetes mellitus are well-recognized complications of tacrolimus-based immunosuppression among adult solid-organ transplant recipients

126
Q

Tacrolimus coadministration with cyclosporine results in additive or synergistic nephrotoxicity; therefore, a delay of at least ________ is required when switching a px from cyclosporine to tacrolimus.

A

24 hours

Since tacrolimus is metabolized mainly by CYP3A, the potential interactions described for cyclosporine apply for tacrolimus as well.

127
Q

ANTI-PROLIFERATIVE AND ANTIMETABOLIC DRUGS

What is a macrocyclic lactone produced by Streptomyces hygroscopicus?

A

Sirolimus (rapamycin; RAPAMUNE)

128
Q

MOA: inhibits T-lympohocyte activation and proliferation downstream of the IL-2 and other T-cell growth factor receptors.

A

MOA of Sirolimus

129
Q

What is a drug whose therapeutic action requires formation of a complex w the immunophilin, FKBP-12?

A

Sirolimus

Also cyclosporine and tacrolimus

130
Q

What complex doesn’t affect calcineurin activity, but binds to and inhibits the mammalian kinase, target of rapamycin (mTOR)?

A

Sirolimus-FKBP-12 complex

131
Q

What is a key enz in cell-cycle progression?

A

Rapamycin (mTOR)

132
Q

Inhibition of Mammalian kinase blocks cell cycle progression at what phase?

A

GJ-S Phase transition

133
Q

What effects lasts for several months after discontinuing therapy, suggesting a tolerizing effect?

A

Sirolimus

in animal models, it inhibits transplant rejection, GVHD, and a variety of autoimmune dses

134
Q

What is absorbed rapidly and reaches a peak bld conc within about 1 hr after a single dose in healthy subjects and within 2 hrs after multiple oral doses in renal transplant px?

A

Sirolimus

135
Q

Systemic availability is approx. ___, and blood conc are proportional to does between _____.

A

15%; 3-12 mg/m^2

Systemic availability is approx. 15%, and blood conc are proportional to does between 3-12 mg/m^2

136
Q

A high-fat meal decreases peak bld conc by how many %?

A

34%

137
Q

How should Sirolimus be taken?

A

Consistently either w or w/o food and bld lvls should be monitored closely

138
Q

What is extensively metabolized by CYP3A4 and is transported by P-glycoprotein?

A

Sirolimus

about 40% of wsirolimus in plasma is bound to protein, especially albumin. the drug partitions into formed elementsof blood, with a blood-to-plasma ratio of 38 in renal transplant px

139
Q

The blood half-life after multiple dosing in stable renal transplant px is:

A

62 hrs

a loading dose of 3x the maintenance dose will provide nearly steady-state conc within 1 day in most px

140
Q

Sirolimus is indicated for prophylaxis of organ transplant rejection in combination therapy with what?

A

A calcineurin inhibitor and glucocorticoids

141
Q

In px experiencing or at high risk for calcineurin inhibitor-associated nephrotoxicity, sirolimus has been used with what to avoid permanent renal damage?

A

sirolimus with glucocorticoids and mycophenolate mofetil

142
Q

The initial dose in px 13 y.o. or older who weigh <40kg should be adjusted based on body surface area (1mg/m2 per day) with a loading dose of:

A

3mg/m2

reduce dose by 1/3 with hepatic impairment px

143
Q

The use of Sirolimus in renal transplant px is associated w a dose-dependent increase in:

A

Serum cholesterol
Triglycerides

that may require tx

144
Q

While immunotherapy w sirolimus per se isn’t nephrotoxic, px treated w cyclosporine + sirolimus have impaired renal fxn compared to

A

cyclosporine + either azathioprine or placebo

renal fxn must be monitored

145
Q

What is a known surgical complication associated with renal transplant, and has occurred significantly often in a dose-dependent fashion in sirolimus-treated px, requiring close post-op follow-up?

A

Lymphocoele

146
Q

Other adverse effects of Sirolimus:

A
  • Hypokalemia or hyperkalemia
  • Anemia
  • Leukopenia
  • Thrombocytopenia

as w other immunosuppressive agents, there is an increased risk of neoplasms, especially lymphomas, and infections

Prophylaxis for Pneumocystis carinii pneumonia and CMV is recommended

147
Q

Other adverse effects of Sirolimus:

A 
Hypokalemia or hyperkalemia
Anemia
Leukopenia
Thrombocytopenia
Fever
GI effects

Increased risk of neoplasms, lymphomas, infxns

148
Q

Sirolimus is a substrate for cytochrome CYP3A4 and is transported by:

A

P-glycoprotein

close attention to interactions w other drugs that metabolized or transported by these proteins is required

149
Q

Coadministration with sirolimus:

A

Cyclosporine and sirolimus: separated by time

Dose adjustment may be required with cyclosporine, diltiazem, or rifampin

No adjustment with acyclovir, digoxin, glyburide, nifedipine, norgestrel/ethinyl estadiol, prednisolone, or sulfamethoxazole/trimethoprim

150
Q

What is a purine antimetabolite and is an imidazolyl derivative of 6-mercaptopurine?

A

Azathioprine (IMURAN)

151
Q

MOA: Following exposure to nucleophiles, s/a glutathione, azathioprine is cleaved to 6-mercaptopurine then is converted to metabolites that inhibit de novo purine synthesis

A

Azathioprine

152
Q

MOA: 6-thio-IMP (fraudulent nucleotide) –> 6-thio-GMP –> 6-thio-GTP which is incorporated into DNA and gene translation is inhibited

Cell proliferation is prevented, inhibiting a variety of lymphocyte fxns

A

Azathioprine

Aza is more potent than 6-mercapto, which reflect differences in drug uptake or pharmacokinetic differences in the resulting metabolites.

153
Q

What is the half-life of azathioprine?

  • well absorbed orally
  • reaches maximum blood lvls w/in 1-2 hrs after admnistration
A

10 mins

154
Q

Half-life of mercaptopurine

A

1 hour

155
Q

What are moderately bound to plasma proteins and are partially dialyzable?

A

Azathioprine and mercaptopurine

156
Q

Both azathioprine and mercaptopurine are rapidly removed from blood by what?

A

Oxidation and methylation in liver and/or erythrocytes

renal clearance is of little impact in biological effectiveness or toxicity, but dose redxn is practiced in px w renal failure

157
Q

What is the strating dose for azathioprine, required to prevent organ rejectionand minimize toxicity which varies?

A

3-5 mg/kg per day

158
Q

Lower initial dose of azathioprine (1mg/kg per day) is used in treating:

A

Rheumatoid arthritis

159
Q

What should be monitored in azathioprine intake?

A

CBC & LFT

160
Q

What is the major side effect of azathioprine?

A

Bone marrow suppression with:
• leukopenia (common)
• thrombocytopenia (less common)
• anemia (uncommon)

Other
• increased susceptibility to infxns (esp varicella, HSV)
• hepatotoxicity
• alopecia
• GI toxicity
• pancreatitis
• increased risk of neoplasia
161
Q

What is an enz of major impt in catabolism of metabolites of azathioprine, and is blocked by allopurinol?

A

Xanthine oxidase

162
Q

What should you do if the same px is using both azathioprine and allopurinol?

A

Azathioprine must be decreased to 25% - 33% of the usual dose

163
Q

Adverse effects resulting from coadministration of azathioprine w other myelosuppression agents or angiotensin converting enzyme inhibitors include:

A
  • leukopenia
  • thrombocytopenia
  • anemia as a result of myelosuppression
164
Q

What is the 2-morpholinoethyl ester of mycophenolic acid (MPA)?

A

Mycophenolate mofetil

165
Q

What is a prodrug that is rapidly hydrolyzed to the active drug, MPA (mycophenolic acid); and is also selective, uncompetitive, and irreversible inhibitor of inosine monophosphate dehydrogenase (IMPDH)?

A

Mycophenolate mofetil

an important enz in de novo pathway of guanine nucleotide synthesis

166
Q

What undergoes rapid and complete metabolism to MPA after oral or IV administration?

A

Mycophenolate mofetil

167
Q

What does MPA do?

A

Selectively inhibits lymphocyte proliferation and fxns, including Ab formation, cellular adhesion, and migration

168
Q

To what is MPA metabolized?

A

Inactive phenolic glucoronide, MPAG

169
Q

What is the half-life of MPA?

A

16 hrs

170
Q

Plasma conc of MPA and MPAG are usually increased in what pxs?

A

Renal insufficiency

171
Q

Where is mycophenolate mofetil typically used in combination and not?

MM - indicated for prophylaxis of transplant rejection

A

Combi: glucocorticoids and calcineurin inhibitor

Not: azathioprine

Renal transplant px: 1g oral/IV over 2 hrs BID (2g per day)
African American renal transplant px & cardiac transplant px: higher dose 1.5g BID (3g per day)

172
Q

Principal toxicities of mycophenolate mofetil are:

A
  • GI
  • Hematologic

Also: increased incidence in some infxns (esp sepsis ass w CMV)

  • diarrhea
  • vomiting
  • leukopenia
173
Q

MM has no untoward effects by combbination therapy with:

A
  • cyclosporine
  • sulfamethoxazole/trimethoprim
  • oral contraceptives
174
Q

Its coadministration leads to decreased absorption of mycophenolate mofetil

A

Antacids containing aluminum or magnesium hydroxide

175
Q

What should not be administered w mycophenolate mofetil bcs it will affect enterohepatic circulation?

A

Cholestyramine

decreases plasma MPA conc, probably by binding free MPA in the intestines

176
Q

What may compete w MPAG for tubular secretion, possibly resulting in increased conc of both MPAG and antiviral agents in the blood?

this may be compounded in px w renal insufficiency

A

Acyclovir and gancyclovir

177
Q

What is used for the tx of GVHD, RA, anticancer therapy, and psoriasis?

A

Methotrexate

178
Q

What are used to treat childhood nephrotic syndrome and variety of malignancies?

A

Cyclophosphamide and chlorambucil

179
Q

Tx for SLE

A

Cyclophosphamide

180
Q

What is a pyrimidine synthesis inhibitor that is indicated for tx of adults w RA?

A

Leflunomide

drug that inhibits dihydroorotate dehydrogenase in the de novo pathways of pyrimidine synthesis; hepatotoxic and can cause fetal injury

181
Q
  • Encountered in transplant of immunocompetent tissue/cell or their precursors (graft) in immunologically crippled hosts (e.g BM transplant)
  • immunocompetent cells of BM recognizes the host cells as foreign and mounts an immune response against them
A

GVHD

the host is immunologically crippled intentionally or not

182
Q

Occurs within days to wks after BM transplantation; prominent manifestations are those from the involvement of skin, liver, intestines; the host is at great risk of opportunistic infxn, being immunologically crippled cell-mediated delayed or cytotoxicity mechanism

A

Acute GVH

183
Q

What may follow acute form or occur insidiously characterized by extensive skin injury (changes similar to systemic sclerosis); chronic liver damage with cholestatic jaundice and GIT damage causing esophageal stricture?

A

Chronic GVH

184
Q
  • host immune system is devastated w involution of thymus and depletion of lymphocytes in LN
  • T lymphocytes are destroyed in donor BM tissue before transfusion virtually eliminates GVH
A

Chronic GVH

185
Q

What reacts against allogeneic stem cells bcs the latter are lacking self-MHC class I molecules and hence fail to deliver the inhibitory signal to what?

A

NK cells

There is great interest in exploiting the ability of NK cells to kill allogeneic hematopoietic cells for treating certain acute leukemias (another ex of GVHD effect)

allogenic NK cells - will not see self-MHC molecules and will not be inhibited but will not cause GVH rxns

186
Q

What is a frequent accompaniment of GVHD?

A

Immunodeficiency

187
Q

Examples of immunodeficiency:

A
  • result of prior tx
  • myeloablative preparation for the graft
  • a delay in repopulation of recipient’s IS
  • attack on the host’s immune cells by grafted lymphocytes
188
Q

Immunologically competent cells or their precursors are transplanted into immunologically crippled recipients and the transferred cells recognize alloAg in the host.

A

GVHD

189
Q

Pathogenic Mechanism of GVHD

A

● Recipients of bone marrow transplants are immunodeficient
because of either their primary disease or prior treatment of the disease with drugs or irradiation.

● When such recipients receive normal bone marrow cells from allogeneic donors, the immunocompetent T cells present in the donor marrow recognize the recipients HLA antigens as foreign and react against them.

● Both CD4+ and CD8+ T cells recognize and attack the host
tissues.

● In clinical practice, GVH disease can be so severe that transplants are done only between HLA-matched donor and recipient.

● However, it is possible that with conventional HLA typing, subtle molecular differences between donor and recipient HLA molecules are not picked, and these may be enough
to trigger GVH reactions.

● For this reason, DNA sequencing methods are now being used for molecular typing of HLA alleles.

● Furthermore, HLA matching will miss minor histocompatibility differences, and these may also be
enough to induce GVH disease.

190
Q

Skin: generalized rash leading to desquamation in some cases

A

Acute GVH

191
Q

Skin: extensive injury with skin appendages destruction and fibrosis of the dermis (resembles systemic sclerosis clinically)

A

Chronic GVH

192
Q

Liver: destruction of small bile ducts resulting to jaundice

A

Acute GVH

193
Q

Liver: cholestatic jaundice

A

Chronic GVH

194
Q

GIT: mucosal ulceration leading to bloody diarrhea

A

Acute GVH

195
Q

GIT: damage to mucosa may cause esophageal strictures

A

Chronic GVH

196
Q

Immune system:

profoundly immunosuppressed
CMV infxn - most important
CMV pneumonitis can be a fatal complication

A

Acute GVH

197
Q

Immune system:

System devastated w involution of thymus abd depletion of lymphocyte in the LN

Recurrent and life-threatening infxns and autoimmunity

A

Chronic GVH

Genetics; Protection II (11 decks)

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