IUSM Indy Inflammation and Immunity/ Immunosuppressive Therapy
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24 terms
Terms | Definitions |
|---|---|
 Discuss the two strategies for drugs that target the immune system. | 1. Modify signaling mediatiors/components of inflammatory process 2. Modify underlying stimulus → remove cause of inflammation (e.g antibiotics) |
| Cytokines bind to . . . a. specific receptors b. G-protein receptors | Specific receptors (mostly tyrosine kinase) |
| Chemokines bind to . . . a. specific receptors b. G-protein receptors | G-protein receptors |
| Name the drug(s) responsible for the following strategy in suppressing immunity/inflammation: inhibition or activation of gene expression. | glucocorticoids |
| Name the drug(s) responsible for the following strategy in suppressing immunity/inflammation: blockade of intracellular signaling. | Cyclosporine; Tacrolimus |
| Name the drug(s) responsible for the following strategy in suppressing immunity/inflammation: receptor antagonism | Antihistamines to block H1 receptors Montelukast and zafirlukast to block LT1 receptors |
| Name the drug(s) responsible for the following strategy in suppressing immunity/inflammation: chemical neutralization. | monoclonal antibodies to TNFα- Infliximab, Adalimumab pseudoreceptor to TNFα- etanercept |
| Name the drug(s) responsible for the following strategy in suppressing immunity/inflammation: costimulation modulation | abatacept |
| Name the drug(s) responsible for the following strategy in suppressing immunity/inflammation: blockade of synthesis | NSAIDs inhibition of cycloxygenase Zileuton inhibition of lypoxygenase |
| Name the drug(s) responsible for the following strategy in suppressing immunity/inflammation: diminish release | Cromolyn to "stabilize" mast cells |
| Name the drug(s) responsible for the following strategy in suppressing immunity/inflammation: inhibit immune response | methotrexate azathioprine mycophenolic acid |
| Methylprednisolone | Action: glucocorticoid Pharmacokinetics •glucocorticoid activity: 4-6Xs more potent than cortisol for anti-inflammatory activity •mineralcorticoid activity: low •t½ = 12-36 hrs Clinical use: high doses i.v. to treat acute transplant rejection |
| Cyclosporine (cyclosporine A) | Action: Calcineurin inhibitor •inhibitor of T-cell mediated immunity •binds to cyclophilin (in T cell) → BLOCKS dephosphorylation of nuclear factor of activated-T cells (NFAT) by calcineurin → NFAT does not enter nucleus → inhibit IL-2 production Pharmacokinetics •metabolized by cytochrome P450 3A (CYP3A) → extensive drug interactions with other drugs metabolized by CYP3A: glucocorticoids, erythromycin, verapamil •GRAPEFRUIT/GRAPEFRUIT JUICE BLOCK CYP3A Clinical use •organ transplants- used in combo with glucocorticoids, antimetabolites • severe rheumatoid arthritis Toxicity •NEPHROTOXICITY in majority •HTN (~50% of renal transplant pts) •tremor •hyperlipidemia •hirsutism, gum hyperplasia |
| Tacrolimus | Action: calcineurin inhibitor •binds to FKBP → inhibits calcineurin → X dephosphorylation of NFAT → X IL-2 production Pharmacokinetics •metabolized by CYP3A (like cyclosporine) Pharmacodynamics •more potent immunosuppressant than cyclosporine Clinical use •transplantation and rescue therapy in patients with rejection episodes Side effects •NEPHROTOXICITY → therapeutic drug MONITORING b/c hi risk for toxicity •neurotoxicity- headace, tremor, seizure |
| Sirolimus (Rapamycin) |  Action: antiproliferator •binds FKBP → blocks mTOR (molecular target of rapamycin) → inhibit ability of IL-2 to enhance division of T cells Metabolism- CYP3A → possible drug interactions Clinical Use •prophylaxis in organ transplant- used with other therapies, esp. in pts with high risk for nephrotoxicity Side effects •hyperlipidemia •leukopenia •thrombocytopenia •AGGRAVATES CYCLOSPORINE RENAL DYSFUNCTION → do NOT coadminister |
| Azathioprine | Action: antimetabolite/antiproliferator •prodrug of purine analog- mercaptopurine: inhibits gene translation Metabolism: slow release → azathiprine-rather than mercaptopurine- favors immunosuppression Clinical Use: immunosuppression Side effects •bone marrow suppression •↑ SUSCEPTIBILITY TO INFECTION |
| Mycophenolic Acid | Action: antimetabolite/antiproliferator •inhibits inosine monophosphate dehydrogenase (IMPDH): rate limiting enzyme in guanosine formation •preferentially affects LYMPHOCYTES 1. lymphocytes depend on IMPDH for purine synthesis- not salvage pathway 2. mycophenolic acid preferentially inhibits Type II IMPDH, which is highly expressed in lymphocytes Clinical use: transplant rejection in combo with glucocorticoids and calcineurin inhibitors (tacrolimus, cyclosporine) but NOT AZATHIOPRINE Side effects •vomiting, diarrhea •leukopenia •↑ risk of infection |
| mycophenolate mofetil | Action: antimetabolite/antiproliferator •PRODRUG for mycophenolic acid with HIGHER F •mycophenolic acid inhibits inosine monophosphate dehydrogenase (IMPDH): rate limiting enzyme in guanosine formation •preferentially affects LYMPHOCYTES 1. lymphocytes depend on IMPDH for purine synthesis- not salvage pathway 2. mycophenolic acid preferentially inhibits Type II IMPDH, which is highly expressed in lymphocytes Clinical use: transplant rejection in combo with glucocorticoids and calcineurin inhibitors (tacrolimus, cyclosporine) but NOT AZATHIOPRINE Side effects •vomiting, diarrhea •leukopenia •↑ risk of infection |
| Methotrexate | Action: folate analog •cytotoxic and antiinflammatory activity Clinical Use •anti-cancer •rheumatoid arthritis •graft versus host dz |
| Anti-thymocyte Globulin (ATG) | Action: antibody •polyclonal antibodies from rabbit injected with thymocytes •antibodies to T-cell antigens → depletes circulating lymphocytes Clinical Use •induction of immunosuppression •acute renal rejection (w/ other immunosuppressant agents) •used for w/drawl of calcineurin inhibitors Side effects •CYTOKINE RELEASE SYNDROME (~ sepsis, serum sickness): fever, headache, nausea/vomiting, malaise, and general weakness |
| muromonab-CD-3 (OKT3) | Action: antibody •mouse monoclonal antibody against human CD3 •depletes available poof of T cells Clinical Use: organ transplant rejection Side effects •CYTOKINE RELEASE SYNDROME •mouse antibody leads to antibody production in host •potentially fatal: pulmonary edema, cardiovascular collapse, arrhythmias |
| Daclizumab | Action: antibody •humanized anti-CD25 mouse monoclonal antibodies •binds to IL-2 receptor on activated T cells (basiliximab has higher affinity) Clinical Use •prophylaxis for renal transplants + w/ other immunosuppresants Major side effects •infection •anaphylactic rxns |
| Basiliximab | Action: antibody •humanized anti-CD25 mouse monoclonal antibodies •binds to IL-2 receptor on activated T cells (higher affinity than daclizumab) Clinical Use •prophylaxis for renal transplants + w/ other immunosuppresants Major side effects •infection •anaphylactic rxns |
| Efalizumab | Action: antibody •humanized IgG1 mAb against CD11a chain of lymphocytes function associated antigen •Blocks T-cell adhesion, trafficking, and activation Clinical use •psoriasis |
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