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28 Cards in this Set
- Front
- Back
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Antithymocyte Immunoglobulin
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Polyclonal antibodies (ATG, Atgam - from horses and Thymoglobulin - rabbit)
-cytotoxic antibodies directed against antigens expressed on human T cells -mechanism of action: antibodies against T cell markers (ex - CD2,3...); T cell clearance from circulation (ie - T cell depletion); modulation of T cell activity; cytotoxic activities (lysis and phagocytosis) clinical use: prevention of acute rejection (induction) and treatment of rejection (rescue); also treatment of GVHD in bone marrow transplants and treatment of severe aplastic anemia Adverse reactions: -cytokine release syndrome (when Ab binds to T cell receptor, activates it), need to pretreat with steroids and benedryl -blood dyscrasias (leukopenia, thrombocytopenia) -anaphylasis (rare) -infections and malignancies! |
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Monoclonal Antibody
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OKT3 (Orthoclone), Basiliximab (Simulect) and Daclizumab (Zenaplax)
-Clinical use = prevention of acute rejection! (and OKT3 treatment of rejection) -Adverse Events: -for OKT3 - same as with polyclonal antibodies -for Basiliximab and Daclizumab - very minimal side effects because not very potent; can use for Hep C patients (don't want to over immunosuppress and reinfect with Hep C) |
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OKT3 (Orthoclone)
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murine monoclonal antibody
-acts by coating circulating T cells resulting in opsonizatoin -modulates T cell antigen receptor CD3 complex --> removal of all CD3 molecules from surface -so, it acts early, like polyclonals Side effects --> like polyclonals (cytokine release syndrome, anaphylaxis, infection, malignancy) |
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Basiliximab (Simulect)
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chimeric (70% human, 30% murine) - recombinant monoclonal antibody
-binds specifically to and blocks the IL-2 receptor (CD25 antigen) -selective for T cells activated by IL-2 -very few side effects (perhaps not that potent) -serum half life (2 doses = 30 to 45 days of CD 25 saturation) |
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Daclizumab (Zenapax)
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humanized IgG (10% murine, 90% human) - recombinant monoclonal antibody
-anti-CD 25 antibody (anti-TAC antibody) -binds with high specificity to the Tac subunit of the high affinity IL-2 complex -Inhibits IL-2 binding -highly specific binding -minimal immunogenicity -prolonged serum half life (5 doses = 120 days of Tac receptor saturation) -very few side effects (perhaps not that potent) |
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Cyclosporine (Sandimmune, Neoral), mechanism of action
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calcineurin inhibitor
-sandimmune was the original, neoral used now -mechanism = inhibits cellular immunity by forming a complex with cyclophilin, the complex inhibits calcineurin, calcineurin is necessary for IL-2 transcription --> impairs IL-2 expression by Th cells |
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Sandimmune Bioavailability
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limited (erratic) oral bioavailability
highly lipid-soluble compound absorption varies widely within and among individuals nonlinear/unpredictable relationship between dose and blood concentration -emulsification by bile salts needed for digestion of oily droplets |
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Cyclosporine Microemulsion
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Neoral
-microemulsion preconcentrate of lipophilic solvent, hydrophilic solvent, surfactant, and antioxidant -contact with GI forms a homogenous, monophasic microemulsion that does not rely on emulsification by bile salts (mimics mixed micellar phase of Sandimmune) -development of microemulsion that acts as aqueous solution has allowed for: -increased absorption of CsA through GI mucosa (increased bioavailbility) -more consistent pattern of absorption -reduced intra-inter individual variability -improved dose linearity (more predictable does response) -increased Cmax and AUC -decreased Tmax -decreased sensitivity to effects of food |
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Therapeutic Plasma Concentrations
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trough concentration (steady-state) = most useful - at first must monitor daily
-therapeutic plasma concentration dependent on: -organ transplanted (higher levels with heart and lung) -time after transplant (1st 3 months = most critical because highest immunosuppression, can get infection) -organ function -clinical condition of patient (ie - concomitant infection) -target trough level: 100 - 400 mg/dL |
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Drug-Drug Interactions of Cyclosporine
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-extensive hepatic metabolism by cytochrome P450 (liver and intestine)
-potential consequences of DDIs = toxicity and therapeutic failure -agents that decrease CsA concentration = anticonvulsants and TB meds -agents that increase CsA concentrations = azole antifungals, calcium channel blockers, antiretrovirals, macrolide antibiotics, cimetidine, sirolimus, and grapefruit juice -must be careful when adding and removing these drugs! -intentional coadministration --> allows reduced total dose of cyclosporine, ultimate reduction in cost, and counteract toxic effects of CsA |
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Cyclosporine adverse reactions
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Nephrotoxicity! (associated with high trough levels, reversible upon discontinuation)
infection hypertension neurologic (tremor, seizure) hirsutism gigival hyperplasia GI effects |
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Tacrolimus, uses
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shares characteristics of CsA but structurally different
-alternative to CsA (as primary or rescue immunosuppressant) -autoimmune disorders |
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Tacrolimus, mechanism
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binds to immunophilins called FK-binding proteins; immunophilin-drug complex binds competitively and inhibits calcineurin; inhibition of calcineurin --> inhibits IL-2 gene transcription
(IL-2 activation needed for growth/proliferation of CTLs) |
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Tacrolimus absorption and metabolism/elimination
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extent and rate of absorption variable in all transplant populations; moderate fat content of food decreases absorption
-primarily eliminated by metabolism, cytochrome p450, impaired liver function increases t1/2, decreases Cl, and increased Ct; pediatric patients clear drug more quickly -renal elimination less than 1% |
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Drug-drug interactions for Tacrolimus
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-substrate for cytochrome P4503A4 and p-glycoprotein; same DDIs as CsA
-hyperglycemia was seen more often because Tacrolimus is more potent than CsA -unique to Tacrolimus = rash and pruritis -common to Tac and CsA = neurological, renal, GI and hyperglycemia |
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Therapeutic concentrations of Tacrolimus
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highly nephrotoxic, avoid IV if possible
-target level 5-20 ng/mL, high concentration = toxic, low concentration = rejection -factors to consider = time after transplant, organ transplanted, clinical conditions) -note - more potent than CsA!!! |
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Azathioprine (Imuran)
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antimetabolite
-inhibits purine synthesis (non-specific, inhibits de novo and salvage pathways) -adverse reaction = leukopenia (very significant, dose limiting) |
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Mycophenolate Mofetil (CellCept), use
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anti-metabolite
prodrug (MPA = active metabolite) -Clincal Use = prevent organ rejection; alternative to azathioprine, used in combination with cyclosporine and corticosteroids |
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Mycophenolate Mofetil (CellCept), mechanism
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inhibits T and B cell proliferation by blocking de novo synthesis of guanosine nucleotides
-noncompetitive, reversible inhibitor of inosine monophosphate dehydrogenase -T/B lymphocytes dependent on de novo pathway for generation of guanosine nucleotides -potential for less myelotoxicity (azathiprine - nonspecific, competitive inhibition) |
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Mycophenolate Mofetil (CellCept), metabolism/elimination
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rapidly converted to MPA (active metabolite) by plasma esterase
-MPA glucuronidated in liver to MPAG (inactive metabolite) -enterohepatic recirculation |
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Mycophenolate Mofetil (CellCept), adverse drug reactions
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principle one = diarrhea (can be dose limiting)
-leukopenia -thrombocytopenia -nausea/vomiting -infections/sepsis -gastritis -CMV tissue invasive disease -fewer side effects than others |
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Mycophenolic acid (Myofortic
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-enteric coated mycophenolic acid; however, no observed decreased GI toxicity because the metabolite is associated with toxicity and has the same metabolite as CellCept; look alike, sound aliek risk
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Sirolimus (Rapamune), uses
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-only FDA approved mTOR inhibitor
-structurally similar to tacrolimus -prophylaxis of organ rejection in patients receiving renal transplants -recommended in combination with cyclosporine and cortiosteroids |
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Sirolimus (Rapamune), mechanism
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binds immunophilin (FKBPs), Sirolimus-FKBP complex inhibits the activation of mTOR (regulatory kinase); this inhibition suppresses cytokine driven T cell proliferation; inhibits progression from G1 to S phase of cell cycle
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Sirolimus (Rapamune) - place in therapy
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patients can get chronic neophrotoxity by exposure to Calcineurin Inhibitors; so, use to prevent chronic rejection; can also use with calcineurin inhibitor intolerance or mycophenolate intolerance
-when used with calcineurin inhibitors --> minimize toxicity (nephrotoxicity), can reduce dose of calcineurin inhibitors -also can facilitate corticosteroid withdrawal |
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Adverse Drug Reactions of Sirolimus
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Decreased Wound Healing!! (so not used immediately post-transplant, might use a weaker induction agent for the first 4-6 weeks)
-hypercholesteroemia -hyperlipidemia -thrombocytopenia/leukopenia But --> no significant effect on GFR! |
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Drug Drug Interactions of Sirolimus
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same as calcineurin inhibitors, but can also increase cyclosporin concentration
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Corticosteroids
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first agent used to prevent rejection in transplanted organs
-blocks lymphocyte proliferation through inhibition of release of IL-1 from macrophages; anti-inflammatory effects -extensive and dose limiting adverse reactions |
