Immunosuppressant and Immunomodulatory Drugs Flashcards
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
Describe the timing and cause of acute rejection
6-12 months post transplant
T cell mediated rejection
Describe the timing and cause of chronic rejection
Months-years after transplant
Due to fibrosis damaging the graft blood vessels
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
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)
Glucocorticoids
MOA
They are steroid hormones that bind intracellular receptors, causing inactivation of proinflammatory and regulatory genes
Decrease number of circulating leukocytes
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
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
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
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.
Azathioprine
Indications
Prophylaxis prevention of graft rejection Autoimmune diseases (RA, Crohn's, MS)
Azathioprine
Adverse Effects
GI effects (nausea, diarrhea, vomiting) Leukopenia Thrombocytopenia Increased infection risk Increased malignancy risk Hepatotoxicity
Azathioprine
Drug Reactions
Reacts with Allopurinol and Febuxostat (Xanthine oxidase inhibitors used in the treatment of gout)
- Causes elevated 6-mercaptopurine levels
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
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
Mycophenolate Mofetil (MMF) Contraindications
Do NOT give MMF to a man or woman of child bearing age who wishes to have children
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
