Immunosuppressive Drugs Use in Organ Transplantation Flashcards
Antiproliferative agents: sirolimus (rapamycin), everolimus
Mechanism: inhibitors of mTOR kinase activity, which prevents CDK2 phosphorylation and thereby blocks cell cycle progression in T cells
Clinical Use:Used in organ transplantation of all kinds, not used on combination with calcineurin inhibitors but as alternate primary drugs with antimetabolites
Toxicities: HLD, myelosyppression, esp thrombocytopenia, also anemia, delayed wound healingm, used in vascular stents. Watch for drug interactions at CYP450s
Notes: sirolimus also binds to FK506BP12 but subsequently mTOR, a kinase necessary to phosphorylate and activate CDK2 for cell cycle progression
Alemtuzumab
Mechanism: hMAB against CD25 on lymphycytes, monocytes, macrophages, NK cells, prolonged T&B depletion
Clinical use: induction, initial or steroid resistant rejection
Toxicities: infusion reactions, including serious respiratory and cardiac, can ppt. autoimmune disease
Notes: used in CLL, promising for transplants
suppression of the immune system results in
increased rates of infection an cancer and in some cases can trigger autoimmunity
Antithymocyte globulin (ATG) and antilymphocyte globulin (ALG)
Mechanism: polyclonal suppression of thymocutes (T) or lymphocytes (T&B, NK)
Clinical Use: induction, initial or steroid resistant rejection, GVH reactions
toxicities: fever, chills, hypotension, serum sickness (type III), sensitization
notes: allows early temporary withdrawal of drugs
Thalidomide
Mechanism: stimulates and changes specificity of T cells, suppresses B cells, stimulates T cells but in a immunomodulatory fashion, ie,changes immune reactivity and sensativity
Clinical Use: Malignancy, GVHR
Toxicities: teratogenic, peripheral neuropathy
Use: used in combination with other drugs for allogeneic bone marrow transplantation
Abatacept
Belatacept
Mechanism: fusion of Fc of IgG1 and CTLA-4 binds to CD80/86 preventing second signal in T-cells, blocking activation
Clinical Use: used for RA, but allows temporary removal of more toxic agents in slow graft response or rejection
Toxicities: Infusion reactions, hypersensativity, nasopharyngitis, URI, nausea, HA
Immunomodulation
immunosuppression
specific induction of tolerance
immunostimulation
Antimetabolites: mycophenolate mofetil
Mechanism: prodrug of mycophenolic acid, an inhibitor of T and B cell inosine monophosphate dehydrogenase in the purine pathway for GMP synthesis
Clinical Use: used as a secondary, ancillary immunosuppressant drug combines with calcineurin inhibitors or antiproliferative agents
Toxicities: leukopenia, diarrhea, nausea, vomiting, infection
Notes: T and B cells are highly dependent on de novo purine synthesis , hence are suppressed
Muronomab-CD3 (OKT-3)
Mechanism: MAb against T cell receptor
Clinical use: induction, initial or steroid resistant rejection
Toxicities: “cytokine release” syndome (pretreat with steroids), infusion reactions, sensitization
Notes: O indicates mouse, but humanized available
Calcineurin inhibitors: cyclosporine (CSA)
tacrolimus (FK-506)
Mechanism: calcineurin (phasphate PP2B) inhibitors blocking signal transduction activating T cells
Clinical Use: primary agents used in organ transplantation of all kinds, commonly in combination with antimetabolites
Toxicities: nephrotoxicity is limiting, neurotoxicity, HTN, HLD, gum hyperplasia (CSA), diabetes (FK-506). Watch for drug interactions at CYP450s
Use: CSA binds to cyclophilin, tacrolimus to FK-506BP12 both peptidyl- prolil- cis/trans- isomerases, before binding to calcineurin
immunosuppressants are used…
for organ transplantation, immune cell cancers and autoimmune diseases; historically requiring lifelong tx after transplantaion
Most current drugs are…
immunosuppressive
Glucocorticoids
Mechanism: suppress distribution and reactivity of lymphoid and myeloid cells, catabolic actions at GRE
Clinical use: early or emergency adjuncts to other suppressants, transient, tapered use
Catabolic state, HTN, diabetogenic, avascular necrosis, osteopenia
Notes: acute use when needed, early or in emergencies
Antimetabolites:
azathioprine
Mechanism: prodrug of 6-MP, an inhibitor of ATP and GTP synthesis
Clinical Use: largely replaced by mycophenolate, but is an alternative, dose reduced with allopurinol
Toxicities: bone marrow suppression, hepatotoxicity, GI toxicity, pancreatitis, alopecia
Notes: can be genetic deficiencies in metabolism by thiopurine methyl-transferase
Daclizumab
Basiliximab
Mechanism: Humanized and chimeric MABs against the Il-2 receptor on T cells
Clinical Use: acute renal rejection
Toxicities: Infusion reactions, tremor, headache, dyspnia, HTN
Use: IL-2R is upregulated on activated T cells, so more selective for active cells
