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Renal System > Immunosuppressive Drugs > Flashcards

Immunosuppressive Drugs Flashcards

1
Q

What is the function of immunosuppressive drugs?

A

Used to dampen the immune response in organ transplantation and autoimmune disease

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2
Q

What are the major classes of immunosuppressive drugs?

A

Calcineurin inhibitors
Antiproliferative/antimetabolic agents
Biological (antibodies)
Glucocorticoids

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3
Q

What is the primary objective of immunosuppressive treatment?

A

Prevent the acute rejection of organ transplant

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4
Q

What is the secondary objective of treatment?

A

Install a tolerance for the transplanted organ

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5
Q

How are the objectives of the immunosuppressive treatment obtained?

A
  1. Down-regulation of the immune system activity to achieve a therapeutic objective
  2. Achieve immunological tolerance: re-educating the body not to reject
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6
Q

What are the steps when administering immunosuppressive treatment?

A
  1. Intensive induction and lower-dose maintenance drug protocols
  2. Greater immunosuppression is required to gain early engraftment
  3. Early high-risk acute rejection is replaced over time by the increased risk of medications’ side effects
  4. Reach a slow reduction of maintenance immunosuppressive drugs
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7
Q

How is early engraftment achieved?

A

Treat established rejection rather than maintain long-term immunosuppression

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8
Q

What are examples of Calcineurin inhibitors?

A

Cyclosporins
Tacrolimus

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9
Q

What are examples of mTOR inhibitors?

A

Sirolimus
Tacrolimus
Everolimus

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10
Q

What are examples of anti-metabolites?

A

Azathioprine
Mycophenolate
Mofetil

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11
Q

What are examples of steroids?

A

Prednisolone
Methylprednisolone

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12
Q

What are examples of monoclonal antibodies?

A

Basiliximab
Alemtuzumab
Rituximab
Adalimumab

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13
Q

What is the the normal pathway of calcineurin?

A
  1. TCR Activation
  2. Phospholipase C Activation –> Ca2+ release
  3. Ca2+ & Calcineurin
  4. Calcineurin + Immunophilin
  5. Dephosphorylation of nuclear factor of activated T - cells (NFAT)
  6. NFAT Translocation
  7. Upregulation of cytokine genes –> Cytokine
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14
Q

At which point of the normal calcineurin pathway do calcineurin inhibitors act?

A

Step 3: When calcineurin acts alongside calcium

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15
Q

What are the PK of calcineurin inhibitors? (4)

A
  1. Narrow therapeutic index
  2. Orally bioavailable
  3. Highly protein bound
  4. Metabolized by CYP3A4
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16
Q

What is the drug interactions of calcineurin inhibitors like?

A

Potential for drug interactions with Sirolimus, an mTOR inhibitor

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17
Q

What is the precaution taken with calcineurin inhibitors because of their low therapeutic index?

A

Therapuetic drug monitoring

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18
Q

What is cyclosporine absorption influenced by?

A

P-glycoprotein (permeability glycoprotein - pump/variability among individuals ABCB1)

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19
Q

What percentage of calcineurin inhibitors is protein-bound?

A

90%

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20
Q

What is the alternative name for Sirolimus?

A

Rapamycin

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21
Q

What is Sirolimus?

A

A macrolide identified in a bacterial strain of STreptomyces that produces a potent antifungal metabolite

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22
Q

What are the medical purposes of mTOR inhibitors?

A

Approved in renal transplantations in combination with other agents

Also used in drug-eluting stents in coronary artery intervention

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23
Q

How does Rapamycin help with stents?

A

Deferred release of antiproliferative drugs such as Rapamycin controls the rapid and undesired cell growth process in the stent

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24
Q

What are the PK of mTOR inhinbitors? (3)

A
  1. Highly protein bound
  2. Adminisered as tablets
  3. Metabolised by CYP3A4, also a substrate for P-glycoprotein
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25
Q

What % of mTOR inhibitor drugs is protein-bound?

A

92%

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26
Q

What happens when Rapamycin binds to FKBP12?

A

Catalyzes peptidyl-prolyl cis/trans isomerization and functions as molecular chaperone

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27
Q

What is FKBP12?

A

A target for Rapamycin

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28
Q

What is Everolimus?

A

A derivative of Sirolimus

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29
Q

What is Tacrolimus?

A

FKB506, which binds to FKBP12

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30
Q

What is the MOA of mTOR inhibitors?

A

Binding of FK binding protein FKBP12 and inhibiting T-cell proliferation and progression from G1 to S phase of the cell cycle

31
Q

What are the adverse effects of mTOR inhibitors?

A

Hyperlipidemia
Risk of kidney failure with combination therapy with Cyclosporine

32
Q

What is Azathioprine (AZA)?

A

A prodrug converted into 6-Mercaptopurine, which is an immunosuppressive medication

33
Q

How does AZA work?

A

Works by interfering with DNA synthesis

34
Q

What is the effect of AZA?

A

Reduces inflammation

35
Q

Where is AZA converted into 6-Mercaptopurine?

A

Gut/ liver

36
Q

When is AZA used?

A

Used in moderate to severe cases of immune reaction
Also used in patients with severe IBD or those who are steroid-resistant or steroid-dependent

37
Q

What is the MOA of AZA?

A
  1. Impair purine biosynthesis
  2. Inhibition of DNA replication and RNA transcription
  3. Limit lymphocytes’ proliferation and increase apoptosis
  4. Inhibit inflammation (TNFa & INFγ)
38
Q

What is the half-life of 6-Mercaptopurine like?

A

Short: 1 to 2 hours

39
Q

What are the drug interactions of 6-Mercaprtopurine?

A

Increased toxicity when combined with Alluprinol

40
Q

What is Alluprinol?

A

A Xanthine oxidase inhibitor

41
Q

What does the metabolism of 6-Mercatopurine depend on?

A

Differences in TPMT activities

42
Q

What are the side effects of 6-Mercaptopurine?

A

Pancreatitis
Major dose-related adverse effect is bone marrow suppression
Vomiting and nausea
Fever, rash, and arthralgia (less common)
Hepatitis (rare)

43
Q

What is MMF?

A

Mycophenolate Mofetil, an anti-metabolite

44
Q

What is MMf hydrolyzed into?

A

Mycophenolic acid

45
Q

What is the medical use of MMF?

A

Prevention of graft rejection in solid organ transplants

46
Q

What are the PK of MMF?

A
  1. Better efficacy and safety profile than AZA
  2. Excellent bioavailabilty
  3. Metabolised via entero-hepatic circulation
47
Q

What is the MOA/target of MMF?

A

It is a non-competitive inhibitor of Inosine monophosphate dehydrogenase (IMDPH)

The effects are more pronounced in rapidly dividing cells

Affects the DNA synthesis

48
Q

What are the PK of glucocorticoids?

A

Good absorption/ excellent bioavailability
Oral or IV

49
Q

What are examples of glucocorticoids?

A

Methylprednisolone
Hydrocortisone

50
Q

When are GC treatments recommended? Why?

A

Addition to organ perfusate solution and pretreatment of transplant donors, to help reduce ischemia-reperfusion injury peri-transplant

51
Q

What is the purpose of GC?

A

To reduce side effects or induce immune tolerance instead of immunosuppression

52
Q

Which kind of GC is used in combination with dexamethasone with inducers of immune-regulatory cells?

A

GCs with low bioavailability and high potency for GC receptors, like Budesonide

53
Q

What is the MOA of steroids?

A
  1. The steroid present in the blood bound to CBG, binds in free form
  2. The main receptor is an intracellular steroid receptor that is associated with heat shock protein HSP90
  3. Receptor complex H - receptor is formed, HSP90 is release
  4. H/R enters the nucleus as a dimer, binds GC response elements on the gene and regulates transcription factor
  5. Protein expression/modulation decreases
54
Q

What are antithymocyte globulins (ATG)?

A

Antibody preparation derived from rabbits or horses hyperimmunized with human thymocytes (non-specific/anti-CD3) –> polyclonal

55
Q

What is an example of anti-CD3-OKT3?

A

Muromonab

56
Q

Which was the first ever monoclonal antibody approved for human use?

A

Muromonab

57
Q

What is Adalimumab?

A

Anti-TNFa

58
Q

What are examples of Anti-CD25?

A

Basilixumab/Daclizumab

59
Q

What is Alemtuzumab?

A

Anti-CD52

60
Q

What is Fingolimod?

A

Sphingosine 1 Phosphate-receptor modulator

61
Q

What is Basiliximab?

A

A chimeric murine/ human monoclonal antibody

62
Q

What is Daclizumab?

A

A chimeric humanized monoclonal antibody

63
Q

What is the target of both Basiliximab and Daclizumab?

A

The alpha chain of IL2 receptor –> CD25

64
Q

What is the MOA of BAsilixumb and Daclizumab?

A

High-affinity for IL2 receptor, CD25, which is a receptor expressed on the surface of the activated T lymphocytes
Works in response to antigenic stimulation only when lymphocytes are activated

65
Q

What is Alemtuzumab?

A

A humanised antibody and CD52

66
Q

How does Alemtuzumab work?

A

Upon T cell activation, CD52 is cleaved and released.

It is activated by other T-cells by binding a special receptor, the Siglec10.

This is an amplification of the immune response; Alemtuzumab blocks CD52

67
Q

What is the main medical purpose of Alemtuzumab?

A

Multiple sclerosis

68
Q

Which drugs are nephrotoxic? (12)

A
  1. Calcineurin inhibitors
  2. NSAIDs
  3. Antibiotics and anti-fungi
  4. Chemotherapy
  5. ACE-inhibitors/ARBs/Renin inhibitors
  6. Orlistat
  7. Statins
  8. Mesalamine
  9. Herbal remedies
  10. Radiocontrast
  11. Heavy metals
  12. Aminoglycosides
69
Q

How can drugs be nephrotoxic? (7)

A
  1. Direct drug nephrotoxicity
  2. Drug-Uromodulin interaction –> cast formation
  3. Intracellular drug accumulation
  4. Increased drug concentration within cells –> transporter competition
  5. Insoluble drug in urine –> crystal formation
  6. Immune drug effects (haptens, molecular mimicry, antibody formation, increased T-cell activity)
  7. Combination of nephrotoxic drugs
70
Q

What is the effect of chronic rapamycin use, as found in animals?

A

Found to cause hyperlipidemia, reduce fat mass, promote glucose intolerance, and diabetes-like syndrome

71
Q

How does chronic rapamycin use causes hyperlipidemia?

A

Coordinately downregulates genes required for lipid uptake and storage in adipose tissue (ATGL, MGL, DAGL)

72
Q

What is the effect of endogenous/ exogenous FKBP38 ligand on mTOR?

A

Blocks mTOR and decreases lipogenesis, and rapamycin interferes by binding FKBP38

73
Q
A

Renal System (24 decks)

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