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IHO Week 5 - WLB > Immunesuppressive Drugs - Regal > Flashcards

Immunesuppressive Drugs - Regal Flashcards

1
Q

What is the general MOA of Anti-Inflammatory Steroids?

A
  • They bind to the cytosolic glucocorticoid receptor (GR)
    • type nuclear receptor that is activated by ligand binding
  • After a hormone binds to the corresponding receptor, the newly formed complex translocates itself into the cell nucleus, where it binds to glucocorticoid response elements (GRE) in the promoter region of the target genes resulting in the regulation of gene expression.
  • Regulates gene transcription in T-cells
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2
Q

What effects on synthesis and/or release of inflammatory mediators do Anti-Inflammatory Steroids have?

A
  • Effects on synthesis and/or release of inflammatory mediators
    • reduce the expression of COX-2 (preferentially over COX-1)
    • inhibit release of arachidonic acid from phospholipids (i.e. stop prostaglandin and leukotriene formation)
    • inhibit degranulation of mast cells & basophils
    • inhibit synthesis and release of TNF, IL-1, IL-2, and IFN
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3
Q

What are the generic names of the 6 Anti-Inflammatory drugs that we need to know?

A
  1. Cortisol
  2. Hydrocortisone
  3. Prednisone
  4. Methylprednisolone
  5. Betamethasone
  6. Dexamethasone
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4
Q

What is the duration of Anti-Inflammatory Steroids?

A
  • Cortisol (Hydrocortisone)
    • short half life: 8-12 hours
  • Betamethasone
    • long half life: 36-72 hours
  • Dexamethasone
    • long half life: 36-72 hours
  • Methylprednisolone:
    • intermediate half life: 12-36 hours
  • Prednisone:
    • intermediate half life: 12-36 hours
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5
Q

What is the distribution of Anti-Inflammatory Steroids?

A
  • Inhaled glucocorticoids
    • prolonged tissue binding in the airway
    • nearly complete hepatic first pass inactivation
  • Glucocorticoids can be administered orally, parenterally, and topically
    • some systemic absorption occurs with all forms
    • metabolized in liver
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6
Q

How are Anti-Inflammatory Steroids eliminated?

A
  • In general:
    • Metabolized in the liver
    • Excreted by the kidney
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7
Q

What are the major toxicities associated with Anti-Inflammatory Steroids fom continued use of large doses?

A
  • Primarily associated with systemic administration
    • increased susceptibility to infection (immunosuppressive)
    • peptic ulceration
    • behavioral disturbances
    • cataracts
    • osteoporosis and vertebral compression fractures
    • inhibition of growth
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8
Q

What are the major toxicities associated with Anti-Inflammatory Steroids fom withdrawal or discontinuation of long term use?

A
  • Primarily associated with systemic administration
    • fever
    • myalgia
    • arthralgia
    • malaise
    • death can occur with hypotension and shock
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9
Q

What are the four synthetic steroids used as anti-inflammatory drugs?

A
  • Betamethasone
  • Dexamethasone
  • Methyloprednisolone
  • Prednisone
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10
Q

What are the two Calcineurin Inhibitors used as Immunosuppressive Drugs that we need to know?

A
  • Cyclosporine
  • Tacrolimus
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11
Q

What is the MOA of Cyclosporine?

A
  • Binds to a cytoplasmic receptor protein called cyclophilin
    • results in the inhibition of calcineurin activit
    • this blocks the dephosphorylation events critical for cytokine gene expression and T-cell activation
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12
Q

What is the MOA of Tacrolimus?

A
  • Binds to a cytoplasmic receptor protein called FKBP (FK506 binding protein)
    • results in the inhibition of calcineurin activity
    • blocks the dephosphorylation events critical for cytokine gene expression and T-cell activation
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13
Q

How is Cyclosporine eliminated?

A
  • Metabolized extensively in the liver
    • potential for numerous drug interactions
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14
Q

What are the major toxicities of Calcineurin Inhibitors, Cyclosporine & Tacrolimus?

A
  • Cyclosporine
    • renal toxicity
      • different from graft rejection in kidney transplantation
    • occurs in as many as 75% of patients being treated with cyclosporine
  • Tacrolimus
    • toxicity similar to cyclosporine with nephrotoxicity
    • 100x more potent than Cyclosporine
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15
Q

What are the two Antiproliferative/Antimetabolic drugs used as Immunosuppressive Drugs that we need to know?

A
  • Sirolimus (a.k.a. Rapamycin)
  • Mycophenolate Mofetil
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16
Q

What is the MOA of Sirolimus?

A
  • Binds to FKBP to inhibit a key enzyme (mTOR) in cell cycle progression
    • blocks cell cycle progression from G1 to S phase
    • prevents the clonal expansion of both B and T lymphocytes
17
Q

What is the MOA of Mycophenolate Mofetil?

A
  • Metabolite of drug inhibits inosine monophosphate dehydrogenase (IMPDH)
    • IMPDH is an important enzyme in the de novo pathway of guanine nucleuotide synthesis
    • B & T cells are highly dependent on this pathway for cell proliferation (other cell types can use salvage pathways)
18
Q

What are the major toxicities of Sirolimus?

A
  • Dose-dependent increase in cholesterol and triglycerides
  • Nephrotoxicity in combination with cyclosporine
  • Increased risk of lymphomas and infections
  • Is a substrate for cytochrome CYP3A4 with the potential for drug interaction
19
Q

What are the major toxicities of Mycophenolate Mofetil?

A
  • Hematologic and gastrointestinal toxicity
  • Leukopenia
  • Diarrhea
  • Vomiting
20
Q

What is the MOA of Anti-thymocyte globulin (ATG)?

A
  • The immunoglobulin binds to the thymocytes in circulation
    • results in lymphopenia and impaired T-cell responses
21
Q

How is Anti-thymocyte globulin (ATG) synthesized?

A

Purified immunoglobulines prepared commercially from hyperimmune serum of animals following immunization with human thymocytes.

22
Q

What are the major toxic effects of Anti-Thymocyte Globulin (ATG)?

A
  • Serum sickness & Nephritis
    • due to the immunoglobulin being recognized as foreign
  • Anaphylaxis rarely occurs
23
Q

What is the MOA of Muromonab-CD3?

A
  • mouse monoclonal antibody binds to the ɛ chain of CD3 glycoprotein that is part of the T-cell receptor complex on T lymphocytes
    • T-cell receptor becomes internalized
    • prevents further antigen recognition
24
Q

What are the major toxic effects of Muromonab-CD3?

A
  • Cytokine release syndrome
    • mild flu-like illness
    • can progress to life-threatening shock
    • administration of glucocorticoids prior to administration of Muromonab-CD3 reduces the symptoms considerably
25
Q

What is the MOA of Daclizumab & Basiliximab?

A
  • Anti-IL-2 receptor (Anti-CD25) antibodies
    • “humanized” in part
  • Binds to the IL-2 receptor present on activated, but not resting, T cells
    • block IL-2 mediated T cell activation events
26
Q

What are the major toxic effects of Daclizumab & Basiliximab?

A
  • Anaphylaxis
  • Lower incidence of:
    • lymphoproliferative disorder
    • opportunistic infections
  • No cytokine release syndrome

IHO Week 5 - WLB (6 decks)

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