Immunopharmacology
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| Innate Immunity: Onset, mechanism of antigen recognition | onset is immediate; antigen recognition via receptors for microbe/viral molecules;
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| Innate Immunity: Cell types/factors | Macrophages, Neutrophils, Mast cells, NK cells, complement, interferon
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| Acquired Immunity: Cell-Mediated and Humoral: Onset, Mechanism of antigen recognition | days to weeks, unique antigen specific receptors (Tcell/Bcell receptors)
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| Acquired Immunity: Cell-mediated, Humoral: Cell Types/factors | APCs, T-lymphocytes, B-lymphocytes
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| Normal Immune Response | designed to protect host/eliminate disease; can recognize "self" antigens; innate/adaptive responses
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| Innate Immune System: First line of defense against antigenic insult | Physical (biochemical: complement/lysozyme/interferons); cellular (neutrophils/monocytes/MQs); Inflammatory response triggered by infxn (neutrophils/monocytes from peripheral circulation enter tissues)
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| Innate Immune System: First line of defense when barrier is breached | comlement and lysozymes are activated, destroys/lyses cell wall of bacteria; ingest/degrade/eliminate pathogens; disease is prevented or duration is decreased
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| Acquired Immunity | takes over when innate can't cope; mobilized by cues from innate; responds to variety of Ag; know's "self;" memory response; divided into Humoral & Cell-Mediated; involves activation of naive T cells
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| Acquired Immunity: mechanisms of recognition | requires APC (dendritic/MQs/Bcells) to process Ag into peptide frags; Peptides bind MHC class II molec w/in APC; MHC presented to CD4+ Tcells w/specific receptor for peptide-MHC complex
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| Acquired Immunity: Tcells require 2 signals to become fully active: | 1. peptide receptor binding; 2. APC T-cell interaction; 1 w/o 2 leads to tolerance
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| Acquired Immunity: Fully activated T cells | differentiate/proliferate into T-helpers (Th1, Th2); Th cells produce cytokines
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| Acquired Immunity: Cell-mediated | involves Th1-mediated activation of MQs and CD8+ cytotoxic lymphocytes (CTLs); Th1 cells secrete cytokines to recruit MQs; local inflam response by MQs can kill intracellular bacteria; CTLs mediate Ag-specific lysis
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| Examples of CTL mediated antigen specific lysis | tumor cells; graft/transplant cells; virally infected cells
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| pCTLs (naive precursor CTLs) require activation by 2 signals: | 1. binding of peptide Ag to APC which binds to TCR on CD* pCTLs; 2. Receptor-ligand interaction of co-stimulaotry molecules
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| Th1 cells produce: | cytokines which stimulate dendritic cells to upregulate co-stimulatory molecules and activate Ag-stimulated CD8 cells
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| Activated CTLs produce: | IL-2
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| In some cases, APCs containing high levels of co-stimulatory molecules can: | activate CD8 cells without Th1 cells present
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| Activated CTLs cause: | Ag-recognition and binding which results in cell lysis
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| Humoral Immunity: Th2 cells | secrete cytokines which stimulate differentiation/proliferation of B cells that become Ab-secreting plasma cells or long-lived memory cells
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| Antigen-specific antibodies | can remove harmful foreign bugs by binding and neutralizing antigens; Ag-Ab complexes activate complement
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| Complement elicits: | a local inflammatory reaction that facilitates Ag removal by phagocytes
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| Fc region of Ab | binds to foreign protein/bacteria before binding to receptors on phagocytic cells for internalization of pathogen
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| Abnormal Immune Response leads to the inability to: | neutralize toxins, inactivate viruses, destroy transformed cells, eliminate pathogens
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| Inappropriate immune responses can result in: | tissue damate (hypersensitivity), reactivity against self (autoimmunity), impaired reactivity to appropriate targets (immunodeficiency)
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| Hypersensitivity | classified as immediate or delayed responses (depends on time to manifest clinical Sx)
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| Immediate hypersensitivity | Ab-mediated; Sx occur w/in min-hrs; Hypersensitivity types I, II, III
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| Delayed hypersensitivity | cell mediated; response can occur 2-3 days following the initial exposure; hypersensitivity type IV
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| Hypersensitivity Type I | dt x-linking of membrane bound IgE (basophils in blood/mast cells in tissue); degranulation (histamine/leukotrienes/eosinophil chemotactic factor); asthma/hay fever/urticaria; severe rxns = anaphylaxis (requires immed med intervention)
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| Hypersensitivity Type II | results from Ag-Ab complexes (IgG or IgM); ex: blood transfusion rxn; can be drug-induced (PCN administered to allergic pt causes anaphylaxis)
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| Hypersensitivity Type III | dt high levels of Ag-Ab complexes; complex deposition and action of lytic enzymes; causes skin rashes/glomerulonephritis/arthritis
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| Hypersensitivity Type IV | delayed-type (DTH); cell-mediated; local inflam response (influx of Ag-nonspecific inflam cells: MQ/neutrophils); cells recruited by Th1 (extravasation/chemotaxis); phagocytic/microbicidal/APC/digestive enzymes; deleterious; intracellular pathogens!!
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| Autoimmunity | body mounts immune response to itself; dt inability to distinguish self from antigen (nonself); activation of self-reactive T/B lymphocytes; diseases are complex dt MHC genetics/environmental conditions/infectious entities/dysfxnl immune regulation
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| 3 Proposed mechanisms for autoimmunity | 1. exposure of self-reactive Tlymphocytes to Ag previously sequestered from immune system; 2. Inappropriate MHC-II expression (inc presentation of self peptide to Thelper cells); 3. Molecular mimicry of invading pathogens
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| Immunodeficiency Diseases | dt abnml immune system; inc susceptibility to infxns; inc duration/severity of disease; can arise from drug Tx; Congenital acquisition (X-linked aggamaglobulinemia/DiGeorge/SCID); or Extrinsic factors (AIDS)
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| Test of Immunocompetence | tests immunologic competence and drug-induced immune dysfxn; used to detect effect of immunosuppressive/immunostimulating agents; seven tests in pathology departments
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| Immunocompetence Test I | DTH testing w/skin antigens used to detect the ability to respond to a recall antigen
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| Immunocompetence Test II | measure of serum immunoglobulins, serum complement, and specific antibodies to natural and acquired antigens
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| Immunocompetence Test III | serial measurements of antibody response after primary immunization or secondary booster injection
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| Immunocompetence Test IV | total circulating lymphocyte count
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| Immunocompetence Test V | measurement of B cells, T cells and subsets (CD4, CD8, CD11a and CD56)
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| Immunocompetence Test VI | In vitro lymphocyte proliferative responses to mitogens or specific antigens of interest; response can be measured by cytokine production of titrated thymidine incorporation
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| Immunocompetence Test VII | mixed lymphocyte reaction, where lymphocytes from one individual are mixed with and proliferated in response to a allogenic lymphocyte from another individual
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| Glucocorticoids | hormonal agents w/lympholytic properties that reduce size and lymphoid content of lymph nodes and spleen; interferes w/cell cycle of activated lymphoid cells; can be cytotoxic to subsets of T cells
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| Glucocorticoids: immunologic effects | no direct cytotoxicity (incl proliferating myeloid/erythroid stem cells in bone marrow); Inhibits production of inflam mediators (PAF/leukotrienes/prostaglandins/histamine/bradykinin); dec chemotaxis & bacter-/fungicidal activity of neutrophils/monocytes
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| Glucocorticoids: leukocyte distribution | causes lymphopenia and neutropenia; dec production of IL-2 and IFN-g vi IL-1 inhibition; dec Ab response (affects cellular immunity > humoral); continued use can dec previously established Ab response
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| Continuous administration of prednisone increases | the fractional catabolic rate of IgG, thus lowering the effective concentration of specific antibodies
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| Corticosteroids used in the treatment of | many conditions dt immunosuppressive/anti-inflammatory properties (idiopathic thrombocytopenia pupura, RA, allergies, bronchial asthma, premedication for transplant recipients)
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| Cyclosporine (gengraf) | fat-soluble peptide antibiotic; used for organ transplant; Tx of graft-v-host dx and some autoimmune disorders
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| Cyclosporine MOA | blocks activation of Tcells in early stage of Ag receptor-induced differentiation; complexes w/cyclophilin & inhibits cytoplasmic phophatase for (calciperuin) Tcell transcription factor (NF-AT)involved in IL-2 synthesis
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| Studies of Cyclosporine have shown | inhibition of gene transcription of IL-2, IL-3, IFN-g, and other factors stimulated by antigen-stimulated Tcells; does not block interaction with antigen or factors on primed T cells
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| Tacrolimus (FK506, Prograf) | macrolide antibiotic produced by Strep tsukubaensis; 10x more potent than cyclosporine; used for organ transplant (solid recipients and standard rejection therapy); atopic dermatitis and psoriasis
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| Tacrolimus (FK506, Prograf) MOA | IV, Oral, Topical; similar to cyclosporine; binds cyclophilin and immunophilin FK-binding ptn (FKBP); inhibits cacineurin (needed for activation of Tcell specific transcription factor (NF-AT)
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| Tacrolimus (FK506, Prograf) Pharmokinetics | dosage determined by trough levels at steady state; Peak [oral] at 1-4hrs; Half-life 9-12hrs (IV); metabolized by CYP450
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| Tacrolimus (FK506, Prograf) Toxic Effects | nephrotoxicity, neurotoxicity, hyperglycemia, hypertension, hyperkalemia, GI symptoms
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| Sirolimus (Rapamune) | derived from Strep hygroscopicus; used alone or in combo (cyclosporine/tacrolimus/mycophenolate mofetil); solid organ transplant; uveoretinitis; steroid-refractory acute/chronic graft-v-host in stem cell transplants
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| Sirolimus (Rapamune) MOA | similar to cyclosporine/tacrolimus; binds immunophilins, inhibits calcineurin, blocks Tcell respone to cytokines, inhibits Bcell/mononuclear cell prolif & immunoglobulin production; inhibits HEMATOPOIETIC recovery after Tx
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| Sirolimus (Rapamune) Pharmokinetics | antagonizes tacrolimus-induced Tcell response; synergistic response w/cyclosporine; **does NOT block IL production by Tcells**
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| Sirolimus (Rapamune) Toxicities | myelosuppression (esp thrombocytopenia); hepatotoxicity; diarrhea; hypertriglyceridemia; HA
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| Interferons | grouped into three families: INF-a, INF-b, INF-g; interact w/cell receptors to produce a variety of different effects
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| INF-a and INF-b | contain type I INFs; acid stable proteins that act on same receptors on target cells; usu induced by viral antigens; more potent than INF-g
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| INF-g | type II INFs; acid-labile protein that acts on a separate receptor target cell; usu produced by activated T-lymphocytes
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| INF immune enhancing properties | esp INF-g; inc APC, MQ, NKC, and cytotoxic Tcell activation; Inhibits cell proliferation; inc expression of MHC-I molecules on cell surfaces (INF-g induces MHC-II, also)
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| INF indications: Hepatitis C | combo therapy; INF-a + Rivabirin
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| INF indications: Cancers | melanoma, renal cell carcinoma, chronic myelogenous leukemia
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| INF indications: Relapsing-remitting multiple sclerosis | INF-b; reduced rate of exacerbation and less severe disease w/minimal side effects
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| INF Toxicities | fever, chills, malaise, myalgia, myelosuppression, HA, depression
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| Mycophenolate mofetil (CellCept) | semisynthetic derivative of mycophenolic acid isolated from Penicillium glaucum; solid organ refractory rejection (cadaver allografts); steroid refractory graft-v-host (bone marrow); lupus, RA, derm
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| Mycophenolate mofetil (CellCept): MOA | Oral, IV; inhibits mitogen and mixed lymphocyte responses; inhibits de novo synthesis of purines; hydrolyzed to mycophenolic acid (active immunosuppressant)
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| Mycophenolate mofetil (CellCept): Toxicity | GI disturbances (N/V/D, abdominal pain); myelosuppression (primary neutropenia)
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| Thalidomide (Thalomid) | sedative drug previously removed from market dt teratogenic effects; useful as immunosuppressant for >40 conditions
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| Thalidomide (Thalomid) MOA | inhibits TNF-a & angiogenesis; dec phagocytosis by neutrophils; inc IL-10 production; alters adhesion molec expression; enhances cell-mediated immunity by Tcell interaction; anti-inflammatory/immunomodulatory
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| Thalidomide Indications | multiple myeloma (initial diagnosis & relapsed-refractory disease; combo w/dexamethasone?); erythema nodosum leprosum (leprosy); skin manifestations of SLE; better response w/combo therapy
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| Thalidomide Toxicity | teratogenesis, peripheral neuropathy, constipation, rash, fatigue, hypothyroidism, inc risk of DVT (thrombosis is particularly frequent in myeloma pts --> use warfarin therapy)
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| Azathioprine (Imuran) | prototype for antimetabolite cytotoxic immunosuppressants; derivative of mercaptopurine; action is mediated by its conversion to an active structural metabolite;
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| Azathioprine: MOA | can block cellular immunity and secondary serum antibody response; kills proliferative cells; interferes w/purine nucleic acid metabolism and lymphocyte prolif following antigenic stimulation; less activity in proliferating cells;
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| Azathioprine: Pharmokinetics | absorbed in GI tract; metabolized to mercaptopurine; excreted in urine; small amts of unchaged drug are excreted renally
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| Azathioprine: Indications | renal allografts/other transplant tissues; acute glomerulonephritis; renal component of SLE, RA, Chron's disease, MS, prednisone-resistant Ab-mediated idiopathic thrombycytopenia purpura and autoimmune hemolytic anemia
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| Azathioprine: Caution and Toxicity | pts taking allopurinol should reduce dose to 1/3-1/4 of normal; bone marrow suppression (usu leukopenia), anemia, thrombocytopenia, skin rask, fever, N/V/D, hepatic dysfxn (inc alk phos/mild jaundice); can be 2x higher in anephric or anuric pts
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| Leflunomide (Arava) | inhibitor of purine synthesis; only FDA drug approved for RA; being studied in combo w/mycophenolate mofetil to treat autoimmune/inflamm skin disorders
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| Leflunomide (Arava): Pharmokinetics | should be started with a loading dose; prodrug; orally active w/an active metabolite (active metabolite half-life is several wks); can be taken every day after SS??
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| Leflunomide (Arava): Toxicity | elevated LFTs; dec risk of liver damage; renal impairment; CV effects (angina, tachycardia), teratogenic
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| Cyclophosphamide (Cytoxan) | ankylating agent; one of most efficacious immunosuppressants for SLE, MS, autoimmune hemolytic anemia, Ab-induced pure red cell aplasia, Wegener's granulomatosis
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| Cyclophosphamide (Cytoxan): MOA | destroys proliferating lymphoid cells, alkylates some resting cells
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| Cyclophosphamide (Cytoxan): Concerns and Toxicity | at high doses it can induce apparent specific tolerance to new antigen; usu combined w/stem cell rescue (transplant) procedures; does NOT prevent graft v. host; Pancytopenia, hemorrhagic cystitis; N/V, cardio-toxic, electrolyte abnormalities
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| Vincristine (oncovin) | vinca alkaloid; idiopathic TP refractory to prednisone
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| Vincristine (oncovin): MOA | though to prevent mast cell degranulation; binds to microtubule units w/in cell; prevents release of histamine and other vasoactive compounds
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| Methotrexate (rheumatrex) | extensive use in RA and graft v. host disease; used in pts w/idiosyncratic rxns to purine antagonists; oral administration
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| Cytarabine (cytosar) | inhibits DNA synthesis; hepatic metabolism; used for bone marrow transplantation, solid organ tumors, leukemia, lymphoma
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| Dactinomycin (cosmegen) | antibiotic, used in renal transplant recipients w/impending rejection
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| Immunosuppressant sites of action: Antigen recognition | Antilymphotyic globulin, monoclonal anti-Tcell antibodies; Rho (D) immune globulin
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| Immunosuppressant sites of action: Proliferation | Prednisone; Cyclosporine; Tacrolimus; Azathioprine; Methotrexate; Dactinomycin; Cyclophosphamide; Antilymphotyic globulin, monoclonal anti-Tcell antibodies
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| Immunosuppressant sites of action: Differentiation/synthesis | Cyclosporine; Tacrolimus; Dactinomycin; Antilymphotyic globulin, monoclonal anti-Tcell antibodies
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| Immunosuppressant sites of action: Tissue injury | Prednisone
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| Other immunosuppressant sites of action | interaction, complement
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| Antibody agents | began w/hybridoma technology; used clinically and diagnostically; development of monoclonal antibody fragments w/specificity and high affinity for antigen; hu
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| Antibody agents and hybridomas | consist of antibody forming cells fused to immortal plasmacytoma cells; stable hybrid cells produce the required amount of cloned antibody in mass culture
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| Humanization of murine monoclonal antibodies | increases half-life; decreased risk of producing antimouse antibodies
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| Antilymphocyte and Antithymocyte Antibodies | heterologous antilymphocyte globulin (ALG) and antithymocyte globulin (ATG)
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| ALG | acts on small, long-lived lymphocytes; w/long use "thymus-dep" lymphocytes depleted; destruction/inactivation of Tcells impairs DTH & cellular immunity; used in combo w/monoclonal Ab for immunosuppression, initial rejection, steroid-resistant rejection
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| ALG: Toxicity | local pain and redness around injection site; anaphylaxis and serum sickness; histocytic lymphomas in buttock; increased risk of cancer
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| ALG and ATG: Indications | suppresses compartments of immune system; manages organ/bone marrow transplants; can be used in combo w/cyclosporine for bone marrow transplant prep (treat high dose 7-10d prior; residual ALG destroys Tcells in donor marrow and dec risk of graft v. host)
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| Immune Globulin (IGIV) | prepared from thousands of healthy donors; no specific antigen targeted; pooling "normalizes" effect on pts immune network
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| Immune Globulin (IGIV): MOA | reduces production of Th cells; Increases suppression of Tcells; causes dec in spontaneous immunogobulin production
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| Immune Globulin (IGIV): Indications | asthma, autoimmune disorders (Kawasaki's disease, subacute SLE, refractory idiopathic TP)
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| Rho (D) Immune Globulin Micro-dose | 15% human IgG w/a higher titer of Ab against Rho (D) antigens on RBCs; Rh+ cells are transferred in 3rd trimester leading to development of erythroblastosis fetalis
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| Sensitization of mother to D-antigen (Rh) occurs at: | time of birth, from miscarriage or from ectopic pregnancies
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| Rho (D) Immune Globulin Micro-dose: Indications | used to treat Rh hemolytic disease of the newborn; Prophylaxis of Rho (D)-negative mothers that have not been immunized to the Rho factor; Treatment for Rh-negative others that have had an abortion, miscarriage or ectopic pregnancy
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| Rho (D) Immune Globulin Micro-dose: Toxicity | usu infrequent, but may cause local discomfort at injection site and rarely a slight temperature increase
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| Hyperimmune Immunoglobulins | preparations of IVIG made from pools of select human or animal donors (they have high-titer antibodies against a SPECIFIC antigen like virus or toxin)
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| Hyperimmune Immunoglobulins: Indications | respiratory syncytial virus, varicella-zoster virus, human herpes virus 3, hepatitis B virus; rabies, tetanus, digoxin overdose; given as antivenom for rattlesnake or coral snake bites
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| Hyperimmune Immunoglobulins: Pharmokinetics | IV administration conveys passive transfer of high-titer antibodies; reduces the risk or severity of the infection
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| Monoclonal Antibodies | gene manipulation of immunoglobulins resulted in humanized and chimeric monoclonal antibodies; several engineered Abs are available on market
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| The murine element remains in the human monoclonal antibodies | complementarity-determining region (CDRs) in heavy and light chains); CDR loops are responsible for Ag-binding capacity of antibodies
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| Chimeric antibodies contain | the antigen-binding murine variable regions and human constant regions
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| Trastuzumab (Herceptin) | recombinant DNA-derived humanized monoclonal antibody; Used for metastatic breast cancer (tumors overexpressing HER-2/neu); induces remission in 15-20% of pts; can be used in combo w/chemotherapy (inc response rate/duration and 1-yr survival)
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| Trastuzumab (Herceptin): MOA | binds to extracellular domain of human epidermal growth factor receptor (HER-2/neu); blocks the natural ligand from binding and down-regulates the receptor
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| Trastuzumab (Herceptin): Pharmokinetics | IV infusion, dosage adjustment for renal impairment; under investigation for use in other tumors that express HER-2
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| Trastuzumab (Herceptin): Toxicity | pain, fever, chills, HA, N/V/D, abdominal discomfort, weakness, back pain, cough, dyspnea, rhinitis, pharyngitis; monitor for cardiac dysfunction during infusion
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| Rituximab (Rituxan) | murine-human monoclonal IgG1 (human Fc) antibody; used for relapse or refractory low-grade of follicular Bcell non-Hodgkin's lymphoma
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| Rituximab (Rituxan): MOA | binds CD20 molecule on normal and malignant Blymphocytes; complement-mediated lysis of cell; antibody-dependent cellular toxicity; induction of apoptosis of malignant lymphoma cells; used in combo w/chemotherapy (synergistic)
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| Rituximab (Rituxan): Toxicities | Bcell depletion (70-80%), fever, chills, asthenia, angioedema, HA, nausea, leukopenia
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| Ibritumomab tuxetan (Zevalin) | anti-CD20 murine monoclonal Ab labeled w/Indium-111 and Yttrium-90; Used for relapse/refractory low-grade, follicular or Bcell non-Hodgkin's lymphoma (NHL); Used in pts w/rituximab-refractory follicular NHL
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| Ibritumomab tuxetan (Zevalin): MOA | binds to and induces apoptosis of Blymphocytes; Tuxetan is a chelator used in specific chelation site of Indium-111 or Yttrium-90; Acts as delivery system to direct radioactive isotopes to target cells; Used in combo w/Rituximab in a 2-step regimen
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| Ibritumomab tuxetan (Zevalin): Toxicity | myelosuppressive (highly); thrombocytopenia, neutropenia, anemia (>60%); chills, fever, pain, HA, N/V, abdominal pain, weakness, dyspnea, infection
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| Daclizumab (Zenapax) | humanized (chimeric) IgG1 that binds to CD25; functions as an interleukin antagonist, Prophylaxis of acute organ rejection in renal transplants; administered 24hrs prior to transplant and 4 separate doses at 2wk intervals
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| Daclizumab (Zenapax): MOA | blocks IL-2 from binding to activated lymphocytes; used in combo w/glucocorticoids and cyclosporine
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| Daclizumab (Zenapax): Toxicity | diarrhea, vomiting, fever, pruritus, respiratory tract infections, UTI
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| Basiliximab (Simulect) | Chimeric human-mouse IgG1 monoclonal antibody; similar to Daclizumab; Used as prophylaxis of acute organ rejection in renal transplants
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| Basiliximab (Simulect): MOA | binds to IL-2 receptor alpha chain on activated lymphocytes; given in 2 IV bolus or IV infusions; Given no more than 2hrs bf transplant and the second dose 4 days after procedure
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| Basiliximab (Simulect): Toxicity | peripheral edema, HTN, atrial fibrillation, fever, HA, insomnia, pain, electrolyte imbalances, UTI, dyspnea, URTI, anemia, tremors
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| Abciximab (ReoPro) | Fab fragment of a murine-human monoclonal antibody; Used to prevent acute cardiac ischemic complications in pts at high risk for re-stenosis; Adjunct to heparin therapy to prevent cardiac ischemia in pts w/unstable angina
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| Abciximab (ReoPro): MOA | Binds to the GPIIb/IIIa receptor on activated platelets resulting in steric hinderance; Inhibits fibrinogen, Von-Wilebrand factor and other adhesive molecules from binding to activated platelets; Prevents platelet aggregation
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| Abciximab (ReoPro): Toxicity | Hypotension, chest pain, minor bleeding, back pain; Monitor CBC, PT, aPTT, platelet count, fibrinogen, guaiac stools
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| Palivizumab (Synagis) | monoclonal antibody; Used in prevention of RSV infection in neonates at risk; reduced frequency of infection and hospitalization by 50%; should be used during on set of RSV season (Oct-Dec)
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| Palivizumab (Synagis): MOA | binds to fusion protein of respiratory syncytial virus (RSV); exhibits neutralizing properties against RSV; Prevents infection in susceptible cells in the airways
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| Infliximab (Remicade) | human-mouse chimeric IgG1 monoclonal antibody (contains human Fc and murine variable regions); Used for Chron's disease of colon and RA (in combo w/Methotrexate)
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| Infliximab (Remicade): MOA | binds to TNF-a (pro-inflammatory cytokine); causes suppression of downstream inflammatory cytokines (IL-1, IL-6, adhesion molecules involved in leukocyte activation and migration)
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| Infliximab (Remicade): Toxicity | increased incidence of lymphoma; HA, fatigue, fever, rash, N/V/D, URTI, cough, infxn, development of antinuclear antibodies, development of new abscess (Chron's); Contraindicated in CHF pts; Monitor hypersensitivity reaction
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| Etanercept (Enbrel) | dimeric fusion protein composed of human IgG1; Used for RA, polyarticlar course juvenile RA, psoriatic arthritis;
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| Etanercept (Enbrel): MOA | binds to both TNF-a and TNF-b; similar effect to infliximab (TNF-a mediated inflam);
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| Etanercept (Enbrel): Pharmokinetics | SQ administration twice weekly; can be used in combo w/methotrexate
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| Etanercept (Enbrel): Toxicity | HA, injection site reaction, RTI, URTI; infection, positive ANA, positive dd-DNA autoantibodies
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| Adalimumab (Humira) | completely *Human IgG1 monoclonal antibody; generated using antibody-phage display technology
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| Adalimumab (Humira): MOA | blocks the interaction of TNF-a with TNF receptors on cell surfaces; does not bind TNF-b; lyses cells expressing TNF-a in presence of complement; reduced levels of CRP, ESR, serum IL-6, MMP-13
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| Adalimumab (Humira): Pharmokinetics | half-life of 2wks; maybe increased by 29-44% in pts taking combo therapy w/methotrexate
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| Alefacept (Amevive) | engineered protein made of CD2-binding portion of LFA-3 fused to human IgG1 Fc region (hinge, Ch1 and Ch2); Used for plaque psoriasis
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| Alefacept (Amevive): MOA | Inhibits activation of T cells by binding to cell surface CD2; Inhibits normal CD2/LFA-3 interactions
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| Alefacept (Amevive): Pharmokinetics and Toxicity | dosed once weekly IV or IM bolus; Dose-dependent reduction in circulating Tcells overall and Tcells in psoriatic plaques; Monitor Tcell levels (*d/c medication if CD4 levels fall below 250cells/uL)
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| Alemtuzumab (Campath) | Humanized IgG1 w/a kappa chain that binds CD52; Used for B cell chronic lymphoyctic leukemia (in pts who fail treatment w/alkylating agents and fludarabine); partial response of 20-30% in clinical trials
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| CD52 | found on normal and malignant B and T lymphocytes, NK cells, monocytes, macrophages, and small population of granulocytes
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| Alemtuzumab:Toxicity | lymphopenia, neutropenia, anemia, thrombocytopenia; Monitor opportunistic infxns and hematologic toxicity
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| Solid organ and bone marrow transplant | requires tissue typing (based on donor/recipient histocompatibility matching; HLA); close matching reduces graft rejection/intensive immunosuppressant therapy
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| Prior to transplant, pt receives | immunosuppressive therapy: ATG, Muromonab-CD3, Daclizumab, or Basiliximab
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| Four types of transplant rejection can occur: Hyperacute | preformed antibodies against donor organ, occurs w/in hrs of transplantation, cannot be stopped by immunosuppressive therapy
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| Four types of transplant rejection can occur: Accelerated | mediated by antibodies and Tcells; cannot be stopped by immunosuppressive therapy
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| Four types of transplant rejection can occur: Acute | involves cellular immunity; occurs w/in days-months of transplantation; can be treated w/general immunosuppressants (azathioprine, mycophenolate mofetil, cyclosporine, tacrolimus, glucocorticoids, cyclophosphamide, methotrexate, rapamycin)
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| Four types of transplant rejection can occur: Chronic | characterized by thickening/fibrosis of vasculature of transplanted organ; both cellular and humoral immunity; occurs w/in months-years after transplant; treated w/same meds used for acute rejecion
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| Allogenic hematopoietic stem cell transplantation is an established treatment for | malignant and non-malignant disease; HLA-matched donor is found; Pt treated w/high-dose chemo/radiation or both & donor's stem cells are transfused
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| A conditioning regimen for bone marrow transplant is used to: | kill cancer cells and suppress the immune system so the pt doesn't reject transplant; a new immune system develops from donor stem cells; rejection is uncommon and is treated by infusion of more stem cells
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| Graft v. host disease in bone marrow transplant | very common dt donor Tcells failing to recognize the pt's tissues as self; acute cases occur w/in 100 days (rash, severe diarrhea, hepatotoxicity); Chronic is after 100 days (requires more therapy)
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| Attempts to prevent Graft v. Host disease in bone marrow transplant | pts are immunosuppressed early in transplant course; usu able to discontinue immunosuppressive therapy w/in 1-2yrs post transplant (unlike solid organ transplant)
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| Effectiveness of immunosuppressive therapy in autoimmune disorders | variable; remission can be obtained and improvement has been shown
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| Plasma immunoabsorption using Protein A columns has been explored to: | remove the immunoreactive antibody, particularly in the formation of immune complexes
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| Immunomodulating Agents | BCG and Levamisole; modulate rather than suppress immune system; inc the immune responsiveness of pts w/immunodeficiency, chronic infections, or cancer;
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| Cytokines | large grp of ptns w/diverse fxns; part of immune system and regulators of hematopoiesis via receptors on target cells; antiproliferative, antimicrobial, antitumor effects;
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| Cytokines and vaccines | adjuvants in clinical trials; GM-CSF (sargrmostim) - thought to induce antitumor immune response resulting in tumor regression
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| INF-a | approved in treatment of several neoplasms (hairy cell leukemia, chronic myelogenous leukemia, malignant melanoma, Kaposi's sarcoma, Hep B/C)
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| INF-b | approved for treatment of relapsing-type MS
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| INF-g | approved for treatment of chronic granulomatous disease
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| IL-2 | used in metastatic renal cell carcinoma and malignant melanoma
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| Cytokine administration/toxicity | most have short serum half-life (minutes); usu administered SQ; fever, flu-like symptoms, anorexia, fatigue, malaise; being studied for inflammatory diseases and septic shock
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| Levamisole (Ergamisol) | 1st used for parasitic infxns; shown to inc magnitude of delayed hypersensitivity (Tcell-mediated immunity); used for Dukes class C colorectal cancer after surgery; when used for Hodgkin's disease it inc Tcells/enhances skin test reactivity; RA efficacy
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| Levamisole MOA | macrophage activation; kills residual tumor cells by activating MQs; May potentiate the effects of 5-FU in adjuvant therapy of colorectal cancer
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| Levamisole: Toxicity | severe agranulocytosis (stops when d/c); nausea, diarrhea, metallic taste; Monitor CBC w/platelets prior to treatment and LFTs every 3 months
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| Bacille Calmette-Guerin (BCG) | a viable strain of Mycobacterium bovis; Used for immunization against TB; non-specific adjuvant/immunostimulant in cancer therapy (esp bladder cancer)
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| Bacille Calmette-Guerin (BCG): MOA | activation of MQs to create more effective killer cells as well as lymphoid cells of immune response
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| Other Adjuvant Agents: Picibanil (OK432), Lentinan, Pachymaran | clinical trials have shown prolonged remission in studied pts; MOA - stimulates MQs to release cytokines including IL-1, CSF, TNF-a
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| Inosiplex (isoprinosine) | immunomodulator; increases NK cell cytotoxicity and Tcell/monocyte function; approved in Europe
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| Cyanoaziridine compounds (azimexon, ciamexon, imexon) | synthetic immunomodulating drugs; under investigation for treatment of AIDS and neoplasia
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| Methylinosin monophosphate | synthetic immunomodulating drug; under investigation of treatment of AIDS and neoplasia
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| Diethyl dithiocarbamate (DTC) | sulfur immunomodulating agent; reduces infxns and slows progression of disease in advanced HIV pts; not yet approved
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| Thymosin | ptn hormones from epithelioid of thymus (bovine/human); conveys Tcell specificity by inducing pre-Tcell maturation to uncommitted lymphoid stem cells and inc number of cells that manifest Tcell surface markers/fxn; Europe and Asia; Tx for HepB/C?
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| Immunologic Rxns to Drug Therapy and Drug Allergy: Type I | immediate drug allergy
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| Immunologic Rxns to Drug Therapy and Drug Allergy: Type II | autoimmune reaction to drugs
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| Immunologic Rxns to Drug Therapy and Drug Allergy: Type III | serum sickness and vasculitic reactions
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| Two groups of drugs that modulate immune function | 1. immune suppressants; 2. immune potentiators
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| Immune suppressants | 1. Antibodies and 2. Drugs [glucocorticoids (prednisone), immunophillin ligands (cyclosporine), cytotoxic (cyclophosphomide), Anti-TNF-a (etenercept), enzyme inhibitors (mycophenolate mofetil)]
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| Immune potentiators | Cytokines (IL-2, Interferon), BCG vaccine, Thymosin
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|
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