Immunosuppressant and Immunomodulatory Drugs Flashcards by Tom O

Describe the timing and cause of hyperacute rejection.

How could you avoid hyperacute rejection?

Occurs within minutes of transplant
Caused by preformed reactive antibodies

Avoid it by crossmatching the blood types and tissues before transplant

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Describe the timing and cause of acute rejection

6-12 months post transplant

T cell mediated rejection

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Describe the timing and cause of chronic rejection

Months-years after transplant

Due to fibrosis damaging the graft blood vessels

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In general, what is the medical approach to immunosuppression in transplant patients?

Triple therapy regimen.
Target 3 different aspects of the immune system to prevent rejection. This also allows you to lower the dose of each regimen, thus decreasing risk of adverse effects

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What are the two glucocorticoids used in immunosuppressive therapy?
Which is a pro-drug and which is an active drug?

Prednisone (prodrug)

Prednisolone (active drug)

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Glucocorticoids

MOA

They are steroid hormones that bind intracellular receptors, causing inactivation of proinflammatory and regulatory genes

Decrease number of circulating leukocytes

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When are high doses of IV steroids (Prednisone/Prednisolone) used?

Acute rejection episodes

Graft vs Host Disease in bone marrow transplant

Treatment of Cytokine Release Syndrome

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Glucocorticoids

Adverse Effects associated with chronic treatment

Increased risk of infection
Hyperglycemia
HTN
Hyperlipidemia
Obesity
High risk of exacerbating preexisting diabetes or developing diabetes
Osteopenia
Cataracts
Growth retardation in kids
Poor wound healing

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Glucocorticoids

How are they typically administered to prevent adverse effects? Describe how cessation of glucocorticoid therapy occurs.

Slow taper over the first month

You should NOT rapidly withdraw from Glucocorticoid therapy due to risk of having an acute adrenal crisis

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Azathioprine

MOA

Prodrug of 6-mercaptopurine.

Then gets converted to 6-TIMP, which inhibits de-novo synthesis of purines.

TIMP also gets metabolized to inhibit Rac1, leading to inhibition of T cell activation.

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Azathioprine

Indications

Prophylaxis prevention of graft rejection
Autoimmune diseases (RA, Crohn's, MS)

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Azathioprine

Adverse Effects

GI effects (nausea, diarrhea, vomiting)
Leukopenia
Thrombocytopenia
Increased infection risk
Increased malignancy risk
Hepatotoxicity

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Azathioprine

Drug Reactions

Reacts with Allopurinol and Febuxostat (Xanthine oxidase inhibitors used in the treatment of gout)
- Causes elevated 6-mercaptopurine levels

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Mycophenolate Mofetil (MMF)
MOA

Prodrug of mycophenolic acid (MMF gets converted to mycophenolic acid via a reaction by a plasma esterase)

Mycophenolic acid inhibits Inosine Monophosphate dehydrogenase (IMPDH) Type II, the rate limiting enzyme in de novo synthesis of purines

Selectively inhibits lymphocyte proliferation

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Mycophenolate Mofetil (MMF)
Adverse Effects

Diarrhea, nausea, vomiting
Leukopenia
Anemia
Embryo/fetal toxicity - congenital abnormalities
Increased infection risk
Increased malignancy risk

Can cause appearance of PML (progressive multifocal leukoencephalopathy) - inflammatory response in brain caused by reactivation of JC virus

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Mycophenolate Mofetil (MMF)
Contraindications

Do NOT give MMF to a man or woman of child bearing age who wishes to have children

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What are the calcineurin inhibitors?

Cyclosporine

Tacrolimus

Calcineurin Inhibitors

Indications

Prevent solid organ rejection
Prevent GvH disease
Several autoimmune disorders (Psoriasis, RA, SKE, Inflammatory bowel)

Cyclosporine

MOA

Cyclosporine binds cyclophilin, which is a peptidylprolyl isomerase, inhibiting the enzyme’s activity.

This complex inhibits Calcineurin, thus inhibiting T cell activation.

What is the normal function of Calcineurin?

Signaling enzyme that activates upon an increase in intracellular Ca2+.
Dephosphorylates inactive NFAT and activates it, activating expression of IL-2 for T cell survival

Tacrolimus

MOA

Tacrolimus binds to FKBP (FK506 binding protein), a peptidylprolyl isomerase, inhibiting the enzyme’s activity.

This complex inhibits Calcineurin, thus inhibiting T cell activation.

Calcineurin Inhibitors

Metabolism

Both Cyclosporine and Tacrolimus are extensively metabolized by CYP3A4

Calcineurin Inhibitors

Adverse Effects

Nephrotoxicity

HTN

What are the mTOR inhibitors?

Sirolimus

Everolimus

Sirolimus and Everolimus | MOA

Both bind FKBP, forming a complex that inhibits the mTAR kinase complex. Inhibits IL-2 mediated signals in T cells, thereby inhibiting T cell proliferation

Sirolimus and Everolimus | Indications

Prophylactic prevention of graft rejection Prevent GvH disease Inhibit restenosis in coronary stents

Sirolimus and Everolimus | Contraindiciations

Pregnancy Liver and lung transplants

What is induction therapy?

Using anti-lymphocytic antibodies to acutely inhibit T cell responses in the recipient at the time of transplant Use either lymphocyte depleting antibodies or functional inhibition antibodies

What is the difference between Lymphocyte Depleting Abs vs. Functional Inhibition Abs in Induction therapy?

Lymphocyte depleting Abs Getting rid of lymphocytes that would attack the graft entirely Functional Inhibition Abs Inhibit the lymphocytes, but do not kill them

Rabbit Anti-thymocyte Globulins | MOA

Actively depletes lymphocytes from blood and lymphoid organs

Rabbit Anti-thymocyte Globulins | Adverse Effects

Cytokine release syndrome (Ab activates T cell and induces cytokines) Leukopenia and increased infections

Alemtuzumab | MOA

Anti-CD52 (attacks T, B cells, macrophages, NK cells, granulocytes) Triggers Ab-mediated lysis of lymphocytes

Alemtuzumab | Adverse Effects

Cytokine release syndrome

Basiliximab | MOA

Antagonist of the IL-2 receptor, inhibiting T cell proliferation Functional inhibitor, does not kill the lymphocytes

When approaching immunosuppressive therapy after organ transplant, how do you design the patient's therapy during the first post-transplant week? Beyond that?

Induction therapy is given intra-operatively and during the first week Maintenance therapy begins after that, including a Glucocorticoid + Cyclosporine/Tacrolimus + Anti-proliferative drug

``` Intravenous Immunoglobulin (IVIG) MOA ```

Purified human Ig from pooled human plasma Prophylactically provides passive immunity to individuals with underlying immunodeficiencies

Hyperimmune Ig | MOA

Similar to IVIG, but it's purified from individuals with high titers against a specific antigen or organism

Rho(D) Immune Globulins | MOA

Antibodies specific for Rh(D) antigen on RBCs Used to prevent hemolytic disease of the newborn in Rh-- women

What are the immune checkpoint inhibitors used?

Ipilimumab | Pembrolizumab/Nivolumab

Ipilimumab | MOA

Monoclonal Ab specific for CTLA4 protein on activated T cells Leads to enhanced T cell activation by preventing CTLA4 from binding CD80/86 and delivering a negative signal

Pembrolizumab and Nivolumab | MOA

Used in metastatic melanoma and non-small cell lung cancer Abs specific for PD1 protein on T cells, blocking the PD1/PD1-L interaction that tumor cells use to evade the immune system