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Foundations of Disease > Exam 2: Immunopharmacology > Flashcards

Exam 2: Immunopharmacology Flashcards

1
Q

Immunopharmacological agents act to…

A

mobilize and/or modify the immune system

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2
Q

Immune Mobilization

A
  • Vaccines
    • Modulates [Ab]
  • Cancer treatment
  • Overcoming immunosuppressed states
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3
Q

Immune Suppression

A

Used for:

  • Transplantation
  • Autoimmune diseases
  • Allergies
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4
Q

Immunopharmacologic

Targets

A
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5
Q

Glucocorticoid

Actions

A

Functions by inhibiting gene expression.

  • Immunosuppressive
    • ⊗ activation of innate and adaptive immune cells
      • T-cells more affected
      • ↓ 1° Ab responses
      • ↓ 2° Ab responses w/ prolonged use
  • Anti-inflammatory
    • ⊗ Expression of inflammatory mediators
      • TNF & interleukins
    • ⊗ Phospholipase A2
      • ↓ Eicosanoid production
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6
Q

Glucocorticoid

Adverse Effects

A
  • Adrenal suppression ⇒ taper therapy to avoid adrenal crisis
  • Cushingoid reactions ⇒ having the constellation of signs and symptoms caused by excess cortisol
  • Mood swings
  • Diabetes
  • ↓ resistance to infections
  • Osteoporosis
  • Cataracts
  • Weight gain
  • HTN
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7
Q

Prednisone

A

Used in combo w/ other immunosuppressants for:

  • Solid organ transplantation
  • Hematopoietic stem cell transplantation
  • Certain autoimmune diseases
    • RA
    • SLE
  • Attenuate allergic reactions
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8
Q

Azathioprine ⇒ Mercaptopurine

Actions

A

Cytotoxic agent

  • Azathioprine (pro-drug) ⇒ Mercaptopurine (anti-metabolite)
    • Converted non-enzymatically in tissues by rxn with sulfhydryls
    • Slow release favors immunosuppressive activity
  • Mercaptopurine interfers with purine nucleic acid synthesis
    • Required for lymphoid cell proliferation
  • Uses:
    • Kidney transplantation
    • Autoimmune diseases
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9
Q

Azathioprine ⇒ Mercaptopurine

Adverse Effects

A
  • Low doses
    • Bone marrow suppression
      • Leukopenia
    • Rash
  • High doses
    • GI disturbances
    • Hepatotoxicity
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10
Q

Azathioprine/Mercaptopurine interacts with…

A

Allopurinol

(Xanthine oxidase inhibitor)

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11
Q

Mycophenolate mofetil (MMF)

Actions

A

“Mycophenolic acid”

Cytotoxic agent

  • Inhibits inosine monophosphate dehydrogenase II (IMPDHII)
    • Isoform expressed in lymphocytes
      • Less toxic to other cells
    • Rate limiting step in guanosine synthesis
      • Blocks de novo purine synthesis
  • Cytostatic and can cause apoptosis in lymphocytes
  • Uses:
    • Kidney transplant
      • More effect than Azathioprine in preventing rejection
      • Prevents chronic rejection in animal models
    • Autoimmune diseases
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12
Q

Mycophenolate mofetil (MMF)

Adverse Effects

A
  • GI disturbances
  • Headache
  • HTN
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13
Q

Methotrexate

A

Cytotoxic agent

  • Folate derivative
  • ⊗ several enzymes responsible for nucleotide synthesis
  • Used for immunosuppresion but not transplantation
    • RA
    • Psoriasis
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14
Q

Cyclophosphamide

A

Cytotoxic agent

  • Alkylates DNA and RNA ⇒ cross-linking of strands
    • ⊗ Protein synthesis
  • Used for immunosuppression but not transplantation
    • Cancers
    • SLE
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15
Q

Cyclosporine (Cyclosporin A)

Actions

A

Inhibition of lymphocyte signaling

  • Decapeptide that binds cyclophilic
  • Complex inhibits Calcineurin
    • Ca2+/calmodulin-dependent protein phosphatase
    • Normally dephosphorylates cytoplasmic transcription factors that controls IL-2 gene
  • Highly selective action in inhibiting activation of T cells
    • Esp. Th cells
  • Uses:
    • Organ transplantation
      • Renal, heart, liver, bone marrow, lung, pancreas
      • Proactively & graft-vs-host reactions
    • Psoriasis
    • RA
    • Rare autoimmune diseases refractive to other treatments
  • Often used in combo with other immunosuppressants ⇒ ↓ effective dose & ↓ adverse effects
    • Corticosteroids
    • Rapamycin
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16
Q

Cyclosporine

Adverse Effects

A
  • Nephrotoxicity
    • Dose-related
    • Caused by vasoconstriction
    • Important to monitor drug levels & creatinine clearance
  • Neurotoxicity
    • Paresthesia, tremor, seizures
  • Hepatotoxicity
  • HTN
  • HLD
17
Q

Cyclosporine

Metabolism

A

Metabolized by cytochrome p450

  • Interpatient variability in response
  • Potential for drug interactions
18
Q

Tacrolimus (FK506)

Actions

A

Inhibition of lymphocyte signaling

  • Macrolide abx with immunosuppressive properties
  • Similar to cyclosporine but 10-100x more potent
  • Binds to FK-binding proteins (FKBP)
  • Complex:
    • Inhibits calcineurin
    • Inhibits IL-3, IL-4, IFN-γ, and TNF-α
  • Uses:
    • 2nd line med after standard therapy fails
      • Organ transplants
      • Autoimmune diseases
    • Standard prophylactic agent used in combo for graft-vs-host
    • Topical prep available
      • Atopic dermatitis
      • Psoriasis
19
Q

Tacrolimus (FK506)

Adverse Effects

A

Similar to cyclosporin but more severe.

Higher potency and solubility.

  • Nephrotoxicity
  • Neurotoxicity
  • Hepatotoxicity
  • HTN
  • HLD
20
Q

Sirolimus (Rapamycin)

Actions

A

Inhibition of lymphocyte signaling.

  • Macrolide abx w/ immunosuppresive activity
  • Binds to FK-binding proteins (FKBP)
  • Mechanism:
    • Inhibits molecular target of rapamycin (mTOR)
      • mTOR normally phosphorylates
        • p70 S6 kinase
          • Involved in protein synthesis
        • PHAS-1
          • ℗ results in release of initiation factor involved in translation
    • Results in inhibition of IL-2 stimulated protein synthesis
    • Arrests lymphocytes in G1 phase
  • Used alone or in combo with other immunosuppressants for solid organ transplant
  • Sirolimus-eluting stents
    • Inhibits proliferation of smooth muscle cells
21
Q

Sirolimus (Rapamycin)

Adverse Effects

A
  • HLD
  • Leukopenia
  • Thrombocytopenia
  • Hepatotoxicity
  • NOT nephrotoxic alone
    • Cyclosporine + sirolimus ⇒ more impaired renal function
      • Likely d/t pharmacokinetic interaction where sirolimus ↑ [cyclosporine]
    • Sirolimus + glucocorticoids + mycophenolate used instead for pts with or high risk for calcineurin inhibitor associated nephrotoxicity
22
Q

Sirolimus (Rapamycin) is metabolized by…

A

cytochrome p450

Potential for drug interactions.

23
Q

OKT3

Actions

A

“Muromonab-CD3”

Selective depletion of T cells

  • Monoclonal Ab against CD3 on T-cells
    • Mouse Ab so body can make Ab against it
  • Depletes T cells through Ab activation of complement
  • Uses:
    • Preparation for transplant
    • Prevent acute rejection
      • Renal, liver, heart
    • Suppresses T-cell mediated responses against transplants
    • Deplete T-cells from donor bone marrow prior to transplant
24
Q

OKT3

Adverse Effects

A
  • Profound but transient immunosuppression
  • Can sometimes activate T cells ⇒ Cytokine release syndrome
    • Occurs if T cells release cytokines before being eliminated
    • Usually occurs after first few doses
    • See fever, myalgia, nausea, diarrhea
25
Q

ATG (Anti-thymocyte Ab)

or

ALG (Anti-lymphocyte Ab)

A

Selective Depletion of T cells

  • Polyclonal Ab against whole human lymphocytes
    • Made by injecting rabbits or larger animals
  • Targets many epitopes
  • Act on long-lived peripheral lymphocytes
    • Little effect on B cells
  • Similar uses to OKT3
    • Preparation for transplantation
    • Acute rejection
    • Preparing donor bone marrow
  • Similar side effects to OKT3 but much broader immunosuppresion b/c polyclonal
26
Q

Anti-CD25 mAb

(Daclizumab)

A

Selective depletion of T-cells

  • Humanized Ab against CD25 ⇒ α-subunit of IL-2 receptor
    • Only expressed on activated T-cells
  • Used for induction
  • Used in combo to prevent rejection
27
Q

Organ Transplantation Treatment

Summary

A

Host vs graft reactions:

  1. Preparation (induction) ⇒ several days - 1 week before
    • Immunosuppressive regimen
      • Daclizumab, ATG, or anti-CD3
  2. Hyperacute rejection ⇒ mins - hours
    • Cannot be stopped by immunosuppressive drugs
  3. Acute rejection ⇒ weeks to months
    • Generally treated with combo of immunosuppressive drugs
      • Calcineurin inhibitor ⇒ cyclosporine or tacrolimus
      • Cell cycle inhibitor ⇒ Mycophenolate mofetil or sirolimus
      • ± Steroids
  4. Chronic rejection ⇒ months - years
    • Cannot be stopped by immunosuppressive drugs
28
Q

Graft vs Host

Disease

A

Major complication of bone marrow and stem cell transplantation

  • Transplanted immune cells attack host cells
  • Start w/ high dose steroids
  • Add drugs:
    • Cytotoxic agents
      • Mycophenolate mofetil
    • Inhibition of lymphocyte signaling
      • Tacrolimus
      • Daclizumab
    • Inhibit cell cycle
      • Sirolimus
29
Q

Immune checkpoint signals used to…

A

inhibit the immune response

30
Q

Checkpoint Inhibitors

A
  • Block immune checkpoint signals
  • Facilitates ability of immune system to attack tumors
  • Consists of:
    • CTLA-4 blockade
    • PD-1 blockade
31
Q

CTLA-4

Blockade

A
  • Cytotoxic T-lymphocyte associated antigen 4 (CTLA-4)
    • Expressed on surface of activated T-cells
    • Competes with CD28 for binding of B7 on APC
    • Prevents co-stimulation of T cells
    • Modulatory mechanism where CTLA-4 attenuates activation of the T-cell
  • Block CTLA-4 wiith Ipilimumab
    • T-cell remains active
    • Enhances immune response to cancer
  • ↑ immune response ⇒ immune-related adverse events common
32
Q

PD-1

Blockade

A
  • T-cells express programed cell death protein (PD-1)
    • Probes cells for PD-L1
    • Cells with PD-L1 avoids attack
      • e.g. human cells
      • Some cancers express PD-L1
  • Nivolumab and Pembrolizumab
    • Humanized monoclonal Ab against PD-1
    • Block interaction with PD-L1
    • Inhibits the inhibition of T-cell proliferation and cytokine production
    • Anti-tumor immune response allowed to proceed
  • Recommended for unresectable or metastatic melanoma that has not responded to ipilimumab/other first line treatments
  • PD-1 blockade more focused @ level of the tumor
    • More favorable adverse effect profile
33
Q

Immunoglobulin Preparations

A
  • IV-IG
  • Rho Immunoglobulin
  • Hyperimmune immunoglobulin
34
Q

Immune Globulin Intravenous

(IV-IG)

A
  • Preparation of immunoglobulin pooled from large population of donors ⇒ normalized serum
  • Used @ low doses in humoral deficiency
  • Used @ high doses
    • Severe asthma
    • Some autoimmune disorders
    • Kawasaki syndrome
35
Q

Rho Immunoglobulin

(Rhogam)

A
  • Human IgG against Rho(D) Ag of RBC
  • Prevents sensitization of Rh⊖ mother
  • Administered to mother within 24-72 hours after birth of Rh⊕ infant
36
Q

Hyperimmune Immunoglobulin

A
  • Made from pools of selected human or animal donors w/ high titer to particular Ag
  • Ex. cytomegalovirus or respiratory syncytial virus

Foundations of Disease (46 decks)

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