Immunomodulatory, Anti-inflammatory and DMARDs Flashcards
BCG (Immucyst)
Live attenuated bacillus calmette-guerin
Interacts with PRR (APCs) > Increased APC activity
Use: bladder cancer
SE: systemic inflammatory response (direct activation of macros) and septic shock (fatal)
Immunostimulant Overview
use normal agonist of immune system
Lack specificity
SE: systemic inflammatory reaction, flu-like symptoms
Applications: vaccination response (adjuvant), chronic infectious disease, immunodeficiency disorders
IL-2 (Aldesleukin, Proleukin)
Lacks specificity, Increased proliferation of activated T cells > IFN-gamma production and increased Tc activity
Use: metastatic melanoma and renal cell carcinoma
SE: capillary leak syndrome, hypotension, reduced organ perfusion (fetal)
IFN-gamma (Actimmune)
Stimulates cell mediated cytotoxic immune response
Use: Treat severe recurrent infections
Immunosuppressant Overview
All have SE: increased risk of infection, cancer with chronic use (PTLD) Drug in class often combined together with differing SEs
Calcineurin inhibitor SE
nephrotoxicity
glucocorticosteroids SEs
metabolic effects of hypertension and diabetes
Anti-metabolites, sirolimus
myelosuppression and anemia
Cyclophosphamide (Cytoxan)
Alkylating agent (bischolorethylamine)
Action: crosslinking DNA/killing prol. cells > prevent clonal expansion + healthy cells
Uses: auto-immune diseases, bone marrow transplant
SE: myelosuppression, nausea, vomiting, infertility
Azathioprine (Imuran)
Metabolized to anti-metabolites 6-MP and 6-TG (purine antagonists)
DNA damage and inhibit purine synthesis
Inactivated by xanthine oxidase
Uses: renal and tissue trasplantation, autoimmune disorders (lupus,RA)
SE: myelosuppression, nausea and vomiting
Mycophenolate mofetil (Cell-Cept)
Hydrolyzed into mycophenolic acid > inhibits inosine monophosphate dehydrogenase > prevent purine synthesis
Use: solid organ transplant, auto-immune diseases
SE: myelosuppression, nausea, vomiting
methotrexate
Antimetabolite > inhibits dihydrofolate reducatse (DHFR) > prevent thymidine + purine nucleotide synthesis
uses: Main drug for rheumatoid arthritis, auto-immune diseases
SE: nausea, mucosal ulcers, modest hepatotoxicity, myelosuppression
leflunomide
metabolized to A77-1726 > inhibits dihydroorotate dehydrogenase > decreased pyrimidine synthesis
19 day half-life + enterohepatic recirculation
Use: rheumatoid arthritis, auto-immune
SE: diarrhea, modest hepatotoxicity, myelosuppression
Glucocorticosteroids Overview
Naturally synthesized in adrenal cortex, anti-infla+immunosuppressive
Induce transcription > annexins > inhibit PLA2 + lipid mediator synthes
Repress transc > IL-2 + IFN-g > reduce Th resp, B cell Ab prod, cyto
Cyclooxygenase, NO synthase, PLA2 > reduce mediator release
IL-8 > reduced recruitment of leukocytes (decreased prostaglandins + leukotrienes)
Prednisone
Glucocorticoid-Immunosuppressive: first line immunosuppresant for solid organ + hematopoietic stem cell transplant
Manage autoimmune, asthma, allergic rections, systemic inflammation
SE: more than 2 weeks of daily use > Cushing’s syndrome, glucose intolerance, ocular disturbance, osteoprosis, hypertens, psych, GI
(Can combine with anti-metabolites)
Calcineurin
calcium dependent phosphatase that dephosphorylates NF-AT > Active NF-AT > drive transcriptoin > IL-2,3,4, FasL, IFN-g, GM-CSF
Activated by TCR > PTKs > PLC > IP3 > increased [Ca2+]
Cyclosporine
Usually combined with other immuno-suppressants/agents
Binds to the immunofilin (proline isomerase) cyclphilin > binds to calcineurin > prvents phosphatase activity = no NF-AT activation
Use: kidney, liver, cardiac transplants, autoimmune disorders (RA), IBD
SE: *nephrotoxicity, hypertension, hyperglycemia, liver dys
Tacrolimus (FK506)
Binds to FKBP12 > binds to calcineurin > prevents NF-AT activation
10X more potent than cyclosporine
Use: Kidney, liver, cardiac transplant, autoimmune (RA)
SE: nephrotoxicity, hypertension, hyperglycemia, liver dys
Sirolimus (rapamycin, Rapamune)
Binds to FKBP12 to prevent mTOR kinase activity > prevent IL-2 activated phosphorylation
Uses: preserve solid organ transplants, steroid-resistant graft vs host disease in hematopoietic stem cell transplants
SE: myelosuppression (potently), hyperlipidemia, hypertension, edema, hepatotoxicity
Antagonizes with tacrolimus (FKB12) but synergize with cyclosporine
Antibody Overview
All require parenteral administration but have long half-lives = weekly-monthly doeses
Uses: neutralize/opsonize antigens, passive immunity, target specific Ag, immunosuppresoin
Rh(D) immune globulin (BayRho-D, WinRho SDF)
human IgG with high titer of Rh(D) Abs > prevents maternal immune response to fetal Rh antigen
Via: opsonization + clearance of D antigens, inhibit activation of maternal naive Rh reactive B cells
Belatocept (Nulojix)
fusion protein that binds to high affinity B7 ligand (CTLA4 mimic, normally found on T cell) with IgG Fc domain > prevents B7 (APC) and CD28 (T cell) interation > anergy of T cell if binds to Ag without costimulation > death
SE: Anemia, neutropenia, peripheral adema, increased infection/cancer
Similiar to calcineurin inhibitors in preventing transplant rejection
Anti-T cell globulin (ATG)
purified IgG (polyclonal animal Ab) against TCR > opsonization of T cells > T cell depletoin (more than a year) SE: Serum sickness, anaphylaxis (repeat usage), cytokine release syndrome (fever, chills, headache, nausea, can be reduced via acetaminophen + antihistamine prior to admin)
CD52
Surface protein on T and B cells, monocytes, macrophages, NK cells
Alemtuzumab (Campath)
Humanized anti-CD52 Ab > depletes broad variety of cells (B, T, Macro, NK (innate + adaptive cells)) > prolonged depletion of cells (1 year)
SE: myelosuppression, flu-like symptoms
Basiliximab (Simulect)
Humanized anti-IL-2 Ab > blocks and opsonizes IL-2 receptor (CD25) on ACTIVATED T cells > Depletes only Ag activated > less robust immuno suppression
SE: Well tolerated
Reduced risk of infection than normal immunosuppressants, good for patients with low-to-moderate risk of rejection
Disease-modifying antirheumatic drugs (DMARDs)
Target the cytokines that promote/amplify the inflammation response = IL-l, IL-6 + TNF-alpha
Infliximab (Remicade)
DMARD: humanized Ab to TNF-alpha > binds > prevents interaction with receptor + reduce systemic/local concentrations
Uses: Rheumatoid arthritis (in combo with methotrexate), Crohn’s disease (in combo with azathioprine)
SE: increased frequency of infections (upper resp, urinary)
Other anti-TNFa agents than infliximab
Adalimumb (Humira): human Ab
Etanercept (Enbrel): fusion protein
Same uses/SE
All DMARD
Anakinra (Kineret)
DMARD: Competitive IL-1 receptor antagonsist (IL-1a analog)
Short half-life requires daily injections
Use: Rheumatoid arthritis
SE: susceptibility to infection
Tofacitinib (Xeljanz)
general Jak kinase inhibitor (enteral) > inhibits all activity of adaptive cytokines (IL-2, IL-4), inflam cyto (IL-6), used for second line therapy following methotrexate (Rheumatoid arthritis)
SE: current dosage is low but higher dose > immunosuppressoin + normal SE = anemia, neutropenia, myelosuppression, increase risk of infection (Herpes zoster)