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Immunopharmacology

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nelso418's version from 2017-04-19 02:48

Section 1

Question Answer
Immunosuppressantsdampen immune responses in organ transplant and autoimmune disease - more susceptible to develop cancer and other diseases
Tolerogensinduce a state of antigen-specific non-responsiveness in organ transplant and autoimmune disease while maintaining immune function - organ transplant
Immunomodulatorsalter the balance of immune elements in autoimmune disease - often in MS
Immunostimulantsaugment immune responses in infection, cancer, and immunodeficiency - used in AIDS
TH1IFN-gamma, IL-2, IL-12 - cell-mediated immunity
TH2IL-4, 5, 6, 10 - humoral immunity
TH17IL-17 - inflammation
T(REG)suppress T cell activation
Antigen Presenting Cells (APCs)dendritic cells, macrophages, B cells
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Hypersensitivity / Drug Allergy

Question Answer
Type I Hypersensitivityimmediate, IgE-mediated (allergies)
Type II Hypersensitivityantibody-mediated (SLE)
Type III Hypersensitivityimmune complex-mediated (RA)
Type IV Hypersensitivitydelayed, cell-mediated (MS)
Type I Drug Allergy IgE against drug/ protein complex (penicillin)
Type II Drug Allergy Drug modifies host protein and elicits an antibody response (procainamide-induced lupus)
Type III Drug Allergy IgG or IgM against drug/protein complex; serum sickness (immune vasculitis)
Type IV Drug Allergy Allergic contact dermatitis from topical drugs or injection site reaction (seen a lot in biologics and poison ivy)
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Immunophilin Ligands/Antimicrobials

Question Answer
Cyclosporine - Neoral ® peptide antibiotic, lipophilic - blocks TH cell activation and IL-2 production - binds cyclophilin and inhibits calcineurin - blocks NFAT activity and expression of NFAT-regulated cytokines
Cyclosporine - Neoral ® PKEPO, IV, CYP3A4; t1/2 = 5-18 h, Requires individualized dosing - Nephrotoxicity
Tacrolimus - Prograf ® Macrolide antibiotic, binds immunophilin FKBP-12 and inhibits calcineurin
Tacrolimus - Prograf ® PKEPO, IV, CYP3A4; t1/2 = 2-36, Requires individualized dosing - Nephrotoxicity, Neoplasia, serious infection
Sirolimus - Rapamune ®blocks IL-2 activity and T cell proliferation - binds FKBP-12, complex inhibits mTOR - effects last after discontinuing - Chemically similar to Tacrolimus
Sirolimus - Rapamune ® PKEPO, rapid, CYP3A4; t1/2 = 62 hours - Neoplasia, serious infection
Everolimus - Zortress ® derivative of sirolimus - slightly shorter half life - transplant rejection prophylaxis
Hydroxychloroquine - Plaquenil ® Hydroxy substitution of chloroquine - Antimalarial with immunosuppressive activity - Decreases antigen processing and loading by increasing pH of sub cellular compartments - reduced T cell activation
Hydroxychloroquine - Plaquenil ® PKEOcular toxicity (monitor annually after 5 years of use)
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Aminosalicylates

Question Answer
Sulfasalazine - Azulfidine ®5-ASA bound by azo (N=N) bond to sulfapyridine; decreases small intestine absorption - Topical anti-inflammatory action - Azo bond cleaved by bacterial azoreductase in colon - releases 5-ASA which has local anti-inflammatory effect - Inhibits COX and lipoxygenase, reduces inflammatory cytokines, inhibits NK cells, scavenges ROS
Sulfasalazine - Azulfidine ® PKENative drug 10% abs, Sulfapyridine 60% abs, 5-ASA 20% abs - Systemic toxicities d/t effect of sulfapyridine (GI distress, rash), Oligospermia, impaired folate absorption
Olsalazine - Dipentum ®2 molecules of 5-ASA bound by an azo - better tolerated than sulfasalazine in UC - can cause diarrhea
Balsalazide - Colazal ®5-ASA bound to a different carrier - better tolerated than sulfasalazine in UC - carrier excreted in feces
Mesalamineaka 5-ASA - the active drug
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Cytotoxic Agents

Question Answer
Cyclophosphamide - Cytoxan ®DNA alkylating agent - blocks proliferation of active lymphocytes - primary metabolite is phosphoramide mustard (liver) - crosslinks DNA to prevent cell replication - more effective on B cell proliferation than other cells
Cyclophosphamide - Cytoxan ® ADRsalopecia; N/V ; cardiotoxicity ; myelosuppression
Azathioprine - Imuran ®Prodrug of 6-mercaptopurine (Purixan ®) - Purine antimetabolite that blocks cell proliferation - converted to 6-MP by non-enzymatic processes - anabolic pathways generate thioguanin metabolites - metabolites interfere witu purine & DNA replication
Azathioprine - Imuran ® PKEPO well absorbed, 6-MP to inactive metabolites via Xanthine oxidase TPMT
Azathioprine - Imuran ® ADRsMyelosuppression, N/V, fever, hepatoxicity
Mycophenolate mofetil - Cellcept ®inhibits de novo guanine nucleotide synthesis - non-competitive inhibitor of inosine monophosphate dehydrogenase (IMPDH) - hydrolyzed to mycophenolic acid (MPA) in liver - Decreases T and B cell proliferation - Mycophenolic acid isolated from mold
Mycophenolate mofetil - Cellcept ® PKEPO, MPA (active) MPAG (inactive)
Mycophenolate mofetil - Cellcept ® ADRsTeratogenic (cat. D), Myelosuppression, HTN, edema, HA, insomnia, fever, GI
Leflunomide - Arava ®Inhibit de novo pyrimidine synthesis - inhibits dihydroorotate dehydrogenase (DHODH) - Causes reduced lymphocyte activation
Teriflunomide - Aubagio ®Inhibit de novo pyrimidine synthesis - inhibits dihydroorotate dehydrogenase (DHODH) - Causes reduced lymphocyte activation
Leflunomide - Arava ® PKEPO, t1/2 18 hours (loading dose)
Leflunomide - Arava ® ADRshepatotoxicity, teratogenic (cat. X)
Teriflunomide - Aubagio ® PKEPO, crosses BBB, no loading dose
Teriflunomide - Aubagio ® ADRshepatotoxicity, myelosuppression, teratogenic (cat. X)
Methotrexate - Trexall ®used at lower doses than those needed in cancer - many immunomodulatory effects - causes intracellular accumulation of AMP, which is released and converted to adenosine (anti-inflammatory) - reduces neutrophil chemotaxis - inhibits proliferation of inflammatory cells and releases pro inflammatory cytokines - Inhibits DHF reductase (not principal mechanism)
Methotrexate - Trexall ® PKEPO (70% absorbed), hepatic metabolism to active metabolites
Methotrexate - Trexall ® ADRsN/V, hepatotoxicity, Myelosuppression, teratogenic (cat. X)
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Misc. Small Molecules

Question Answer
Dimethyl fumarate - Tecfidera ®Methyl ester of fumaric acid - DMF -> MMF -> Nrf-2 transcriptional program - decreased oxidative stress - protects neurons from inflammation
Dimethyl fumarate - Tecfidera ® ADRslymphopenia (risk of infection), flushing, GI distress, hepatotoxicity
Glatiramer acetate - Copaxone ®Mixture of random polypeptides of 4 amino acids (alanine, glutamic acid, lysine, tyrosine) that is antigenic ally similar to MBP - Decreases immune response to myelin antigens by activating suppressor T (T-REG cells) cells that migrate to CNS
Glatiramer acetate - Copaxone ® ADRsinjection site reactions, chest pain
Fingolimod HCl - Gilenya ®Derived from fungal antibiotic myriocin - Sphingosine 1-phosphate (S1P) receptor antagonist - S1PR controls lymphocyte exit from lymph nodes - Fingolimod phosphate binds S1PR and decreases circulating lymphocytes (peripheral and CNS)
Fingolimod HCl - Gilenya ® PKECYP4F2 to active metabolite; 2D6, 3A4 involved
Fingolimod HCl - Gilenya ® ADRsCardiotoxicity, hepatotoxicity, macular edema
Tofacitinib - Xeljanz ®Janus kinase inhibitor (JAK) - interrupts JAK-STAT signaling pathway (JAK3) - Downstream of interleukin and interferon receptors - reduces NK cells, serum antibodies, C-reactive protein; increases B cells
Tofacitinib - Xeljanz ® PKEPO, rapid 74% bioavail. - CYP3A4 and 2C19 to inactive metab
Tofacitinib - Xeljanz ® ADRsMalignancy, serious infection
Apremilast - Otezla ®Phosphodiesterase 4 (PDE4) inhibitor - PDE 4 specific for cAMP -> increased intracellular cAMP - regulation of inflammatory mediators: decreased NOS, TNF-alpha, IL-23; increased IL-10 (anti-inflammatory)
Apremilast - Otezla ® PKECYP3A4 to inactive metabolites
Apremilast - Otezla ® ADRsdepression, unexplained weight loss
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Monoclonal Antibodies Naming

Question Answer
-imabmouse/human chimera
-zumabhumanized
-umabfully human
-ceptfusion protein
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Targeted Antibodies

Question Answer
Etanercept - Enbrel ®, Erelzi ®Anti-TNFalpha
Infliximab - Remicade ®, Inflectra ®Anti-TNFalpha
Adalimumab - Humira ®, Amjevita ®Anti-TNFalpha
Certolizumab - Cimzia ®Anti-TNFalpha
Golimumab - Simponi ®Anti-TNFalpha
Natalizumab - Tysabri ®Anti-Integrin
Vedolizumab - Entyvio ®Anti-Integrin
Tocilizumab - Actemra ®Anti-IL
Ustekinumab - Stelara ®Anti-IL
Secukinumab - Cosentyx ®Anti-IL
Ixekizumab - Taltz ®Anti-IL
Basiliximab - Simulect ®Anti-IL
Daclizumab - Zinbryta ®Anti-IL
Alemtuzumab - Campath ®, Lemtrada ®Misc.
Rituximab - Rituxan ®Misc.
Belimumab - Benlysta ®Misc.
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Anti-TNFalpha

Question Answer
Etanercept - Enbrel ®, Erelzi ®Anti-TNFalpha recombinant fusion protein - TNF receptor linked to human IgG Fc domain - binds to and inhibits activity of soluble TNFalpha
Etanercept - Enbrel ®, Erelzi ® ADRsPotential teratogen (currently cat. B)
Certolizumab pegol - Cimzia ®Humanized anti-TNFalpha antibody fragment conjugated to PEG - does not fix complement or cause antibody-mediated hypersensitivity (Type II hypersensitivity)
Infliximab - Remicade ®, Inflectra ®Chimeric anti-TNFalpha antibody - binds soluble and possibly membrane bound TNF alpha - reverse signaling that reduces cytokine release
Adalimumab - Humira ®, Amjevita ®fully human anti-TNFalpha antibody
Golimumab - Simponi ®fully human anti-TNFalpha antibody
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Anti-IL

Question Answer
Tocilizumab - Actemra ®Humanized anti-IL6 receptor antibody - binds to soluble and membrane bound IL-6 receptors - inhibits IL-6 mediated signaling on B lymphocytes - decreases B lymphocyte activation
Tocilizumab - Actemra ® ADRsMay increase activity of some CYPs, Infection, hepatotoxicity, demyelinating diseases (Rare)
Ustekinumab - Stelara ®Anti-IL 12, 23 antibody - reduces activation of NK and CD4+ T cells and inhibits cytokines
Ustekinumab - Stelara ® ADRsInfection, reversible leukoencephalopathy (rare)
Secukinumab - Cosentyx ®Anti-IL 17 antibody
Secukinumab - Cosentyx ® ADRsInfection (usually non serious), new onset IBD
Ixekizumab - Taltz ®Anti-IL 17 antibody for psoriasis
Basilizimab - Simulect ®Anti-IL 2 receptor antibody - prevents T cell activation
Basilizimab - Simulect ® ADRsOpportunistic infection
Daclizumab - Zinbryta ®Anti-IL 2 receptor antibody - prevents T cell and NK cell activation
Daclizumab - Zinbryta ® ADRsHepatotoxicity, infection, injection site reactions
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Anti-Integrins

Question Answer
Natalizumab - Tysabri ®Anti-alpha 4 integrin antibody (expressed by most leukocytes) - Inhibits leukocyte adhesion which reduces chemotaxis
Natalizumab - Tysabri ® ADRsRisk of progressive leukoencephalopathy
Vedolizumab - Entyvio ®Anti-alpha-4-beta-7 integrin antibody (specific to GI tract) - Inhibits migration of T cells into inflamed GI tissue
Vedolizumab - Entyvio ® ADRsHepatotoxicity
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Misc.

Question Answer
Alemtuzumab - Lemtrada ®Anti-CD52 antibody - CD52 is a cell surface protein found on B and T lymphocytes, NK cells, monocytes, macrophages - Depletes these cells by direct antibody-dependent lysis (ADCC)
Alemtuzumab - Lemtrada ® ADRsAutoimmune (thyroid) conditions, infusion reactions, malignancy, myelosuppression
Rituximab - Rituxan ®Anti-CD20 antibody - CD20 is a cell surface protein found on B cells - depletes B cells by complement activation and ADCC
Rituximab - Rituxan ® ADRsInfusion reactions, infection
Belimumab - Benlysta ®Anti-BLyS antibody - BLyS is a soluble B cell stimulator protein - prevents survival of B cells
Belimumab - Benlysta ® ADRsInfusion reactions, depression/mood changes
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Tolerogens

Question Answer
Abatacept - Orencia ®Binds CD80 / 86 and prevents T cell activation
Belatacept - Nulojix ®Mechanism identical to abatacept
Belatacept - Nulojix ® ADRsSerious infection, malignancy
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Interleukins

Question Answer
Aldesleukin - Proleukin ®Recombinant IL-2 - stimulates biologic effect of endogenous IL-2 - indicated in renal cell carcinoma and melanoma - impaired neutrophil function, capillary leak syndrome
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Osteo Biologics

Question Answer
Denosumab - Prolia ®Anti-RANKL antibody - binds RANKL and prevents its interaction with RANK - Inhibits osteoclast differentiation/function - decreases bone resorption and increases bone mass/strength
Denosumab - Prolia ® PKERequires supplementation with Calcium and Vit. D
Denosumab - Prolia ® ADRshypocalcemia, infection, rash, osteonecrosis (rare)
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Asthma Biologics

Question Answer
Mepolizumab - Nucala ®Anti-IL-5 receptor antibody - IL-5 responsible for recruitment of eosinophils - reduces eosinophil production and survival
Mepolizumab - Nucala ® ADRsslight risk of infection
Reslizumab - Cinqair ®same MOA as mepolizumab
Reslizumab - Cinqair ® ADRsAnaphylaxis, infection, malignancy
Omalizumab - Xolair ®Anti-IgE antibody - prevents binding of IgE to mast cells and basophils, reducing early and late phase allergic response - reduces circulating IgE
Omalizumab - Xolair ® ADRsAnaphylaxis (rare), infection
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Cystic Fibrosis Agents

Question Answer
Ivacaftor - Kalydeco ®CFTR potentiator increases channel opening and Cl transport of G551D-CFTR - Indicated for CF G551D mutants
Lumacaftor + Ivacaftor - Orkambi ®CFTR conformation stabilizer - stabilizes conformation of F508del-CFTR
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