immunopharmacology Flashcards

Question

Methotrexate

Answer 1

Mech. of action: antimetabolite, Inhibition of DHF-reductase and depletion of folic acid leads to the blockade of DNA synthesis. The anti-inflammatory mechanism is likely the inhibition of AICAR transformilase by MTX-polyglutamates ◦ Inhibits several enzymes, including: ◦ dihydrofolate-reductase ◦ 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) formyltransferase (ATIC) -AICAR inhibits competitively AMP deaminase - AMP accumulation, AMP is converted extracellular to adenosine which is a potent inhibitor of inflammation - thymidylate synthase accumulation of AICAR intracellularly and adenosine extracellularly  inhibition of both B and T-cell activation (interestingly TNF) macrophages and dendritic cells secondary effects on PMC chemotaxis -stimulates apoptosis in inflamatory cells -inhibits proinflammatory cytokines linked to rheumatoid synovitis  upregulates adenosine receptors)  The polyglutamates of MTX persist in cells longer  In autoimmune diseases (RA, psoriasis – and other dermatological diseases, SLE, IBDs, JCA, PA, AS, POLYMYOSITIS, Dermatomyositis, Wegeners granulomatosis, giant cell arteritis, vasculitis) If it is needed it can be given sc. as well. oral bioavailability is 70% hydroxychloroguin can reduce the excretion and increase the tubular reabsorption 30%bile excretion but primarily in kidney Adverse effects: #alopecia #leukopenia, anemia  Liver enzyme elevation, hepatotoxocity  Fibrotic pneumonitis (hypersensitivity reaction)  Infection  GI problems (mucositis, stomatitis, diarrhea, ulcer, nausea)  (BM suppression)  Liver toxicity can be alleviated by leucovorin administration (next day after) or folic acid - reduce efficacy 10% teratogenic

Answer 2

 Mech. of action: They are inhibitors of dihydroorotate-dehydrogenase – this blocks the pyrimidin synthesis. Arrest in G1 -phase. Teriflunomid is the activ metabolite of leflunomide.  They block T-cell proliferation and AB production of B-cells secondarily increase in IL-10receptor mRNA; decrease in IL-8 receptor mRNA, an decrreased NF-kB activation (TNFa dependent)  Leflunomide is registered for RA and similarly as effective as MTX. Teriflunomide is the active metabolite of leflunomide, it is used for remitting-relapsing MS  They are orally given T1/2 is 2 weeks , enterohepaticcirculation also of active metabolite Cholestyramine can accelerate the excretion  Adverse effects: liver enzyme elevation (up to sever liver dysfunction) diarrhea, skin exanthemas, alopecia, mild hypertension, weight gain increased BP, leukopenia and thrombocytopenia occur rarely

Answer 3

 It is transformed in the body to 6-mercaptopurine (6-MP) (book: 6-thioguanine). 6-MP turns to thio-IMP: it blocks AMP and GMP synthesis. ◦ Inhibit phosphoribosyl-pyrophosphate-amido-transferase (purine synthesis) ◦ Inhibit purine-base salvage ◦ Incorporates into nucleic acids  It is not known why azathioprin is a more specific immunosuppressive agent than 6-MP (better uptake or transformation in lymphocytes?) blocks IL-2 secretion  Kinetic: Azathiopron is given orally or parenterally, Thio-IMP is catabolized by xanthin-oxydase. (Cave allopurinol!) rapid metabolizeres metabolise the drug 4x faster (bimodal metabolism in humans)  It mainly blocks cellular immunity  Use: kidney transplantations, IBDs, SLE, vasculitis diseases, (RA), PA, polymyositis, behcet disease, vasculitius  Adverse effects: BM suppression, liver toxicity (rarely: liver vein occlusion syndrome) GI disturbances, infection risk, lymphomas, allergic reaction

Answer 4

 It is isolated from Penicillium sp.  Mycophenolate is converted to mycophenolic acid (active form), blocks inosine-monophosphate-dehydrogenase (de novo GMP synthesis). Lymphocyte (b-cell +T-cell) cannot use salvage-way for nucleotide uptake (they are extremely sensitive to de-novo blockade), blocks proliferation interferes with leukocyte adhesion downstream by inhibiting E-selectin and P-selectin, and intracellular adhesion molecule 1  Use: organ transplantations (1st of choice for heart, liver and kidney). Off label: GVH, SLE, RA, nephritis, myasthenia, psoriasis, wegeners granulomatosisa ) prevent chronic allograft vasculopathy in cardiac recioient patients (1st line), acute and chronic GVH, generally an alternative to cyclosporin and tacrolimus for patients who do not tolerate those  Adverse effects: BM suppression, GI disorders, hypertension, nausea, dyspepsia, hepatotoxicity , infection and rarely malignancy, prevent chronic

Answer 5

Derived from mustard gas, the group called bis(chlorethyl)amine Prodrug: it turns in more steps in the body into phosphoramide mustard (the active form) and into acrolein (inactive but toxic) Phosphoramide mustard is a bifunctional alkytating agent. It alkylates DNA mostly on N7 of guanosine. It forms cross-links inside of DNA chain or between the two chains to prevent cell replication It inhibits both T and B cells by 30-40% Used: in SLE, systemic sclerosis, vasculitis diseases, wegeners granulomatosis autoimmune glomerulonephritis, AI hemolytic anemia, Transplant stem cell procedures, but does not prevent GVH disease, ``` Adverse effects: BM suppression (pancytopenia), oligospermia, ovarian dysfunction, GI, cardiac toxicity, hemorrhagic cystitis (akrolein), teratogenity and possible mutagenity, may cause hemorrhagic cystitis (treated with mesna), electrolyte disturbances ```

Answer 6

 It is isolated from the blood of healthy donors and iv. given.  The IG mix can be used for the treatment of IG deficit. It can also be used as an immune modulator: to neutralize superantigens and autoantibodies, to block Fc receptors of macrophages, to inhibit the complement and immuncomplex mediated tissue destruction.  Use: ITP, Kawasaki-Sy., Guillain-Barre Sy., Polymyositis, Vasculitis, SLE and IG deficit  Adverse effects: allergic reactions  Anti Rh0 (D): concentrated solution from human source. It must be given after delivery of Rh+ baby of Rh- mother to suppress own antibody generation

Answer 7

 They are isolated from blood of rabbits or horses immunized by human lymphocytes or thymocytes. It kills and blocks lymphocytes in the body.  Use: it is the most effective agents against acute rejection of grafts after transplantation. It is used if the possibility of rejection is high. In BM transplantation the pretreatment of the graft by ALG reduces the possibility of GVH.  Adverse effects: dyspnoe, serumdisease, fever, GI disturbances  (Hyperimmunglobulins (human or animal) are used against viral infections (passive immunization for CMV, VZV, HBV, Rabies) or for toxicology (dioxin, snake venoms etc.). For RSV (palivizumab) and against B toxin of C. difficile (bezlotoxumab) monoclonal AB are available. )

Answer 8

100% murine Mouse

Answer 9

75% human 25% murine Chimera

Answer 10

95% human 5 % murin Humanized

Answer 11

100% human Human

Answer 12

Monoclonal recombinant murine AB against CD3 coreceptor of TCR. it is older than the nomenclature. (-momab) It reduces T-cell count rapidly.  Use: It is given for kidney transplantation against acute rejection  Adverse effect: cytokine release syndrome (Flu like symptoms, sometimes shock)

Answer 13

Antibody against IL-2 receptor. against T-cell. It inhibits the activation of lymphocytes but it does not kill them.  Use: it can be used in solid organ transplantations against acute rejection, but it is less effective than ALG or ATG  Adverse effects: GI symptoms

Answer 14

 They bind to CD20 antigen both of normal and malignant B-cells. They dramatically reduce (after one treatment) B-cell count for many (6-9) months (true for non malignant cases) through complement and cell (macrophage, neutrophil or NK) mediated pathway. They can cause apoptosis as well.  Use: originally rituximab was developed for low malignant B-cellular lymphomas and CLL. In RA it is given periodically (2 doses in 2 weeks and after 6 month break). It is also registered for vasculitis diseases. Off label it can be used for more therapy resistant autoimmune diseases and organtranstplantation. Ocrelizumab is registered for MS (also for progressive type).  Adverse effects: infusion-reactions (steroid, paracetamol and antihistamine prophylaxis needed), infections (serious viral, bacterial or fungal), malignancies, infusion reaction, arrhythmias (rare), angina (rare), late onset neutropenia, rash, HBV screening, reactivation of tuberculosis, lymphoma, fatal mucocutaneous reaction, cytopenias ◦ Broad off-label use  Other CD20 antibodies for treatment of tumors: Obinutuzumab, Ofatumumab, Y90- Ibritumomab-tiuxetan, Veltuzumab

Answer 15

 Antibody against CD52 that is abundant on B-, T-, NK cells and macrophages. Originally it was developed for B-cellular CLL (withdrawn). Today it is indicated for MS. It depletes autoimmune B and T cells. The repopulation normalizes immune balance.  Adverse effect: BM suppression

Answer 16

 Fusionprotein of 2 TNFαR and Fc  Use: sc. 1-2 x / week ANTI-TNFa TREATMENT Ethanercept is not effective in IBDs – it could worsen the symptoms possible because it cannot neutralize bound TNFα. In RA, JIA, Bechterew, psoriasis all TNFα blockers have similar effectivity. They could be used for uveitis as well. In RA they are mostly combined with MTX, but monotherapy is also possible Side effects: risk of infections (tuberculosis, opportunistic infections, activation of latent viral hepatitis), infections site and infusion reactions, allergy

Answer 17

 Chimera AB IgG1 binds soluble and possible membrane-bound TNFa. (same as adalimumab)  Use: iv. once / 2 month half life is 9-12 days  Biosimilars are available ANTI-TNFa TREATMENT registered for RA, JIA, Bechterew’s disease (ankylosing spondylitis), psoriasis and both IBDs, PsA off label : vasculitis (different types), uveitis, sarcoidosis, In RA they are mostly combined with MTX, but monotherapy is also possible (or antimalaria drugs, azathioprine, leflunomide, cyclosporin) Neutralizing AB formation is possible (more often against infliximab) Side effects: risk of infections (tuberculosis, opportunistic infections, activation of latent viral hepatitis), infections site and infusion reactions, allergy MTX reduces the occurence of human antichimeric antibodies

Answer 18

Human AB IgG1, binds with soluble TNFa and prevents interaction with p55 and p75 cell surface receptor this results in downregulation of macrophage and T-cell function Use sc. once/2 wekks ANTI-TNFa TREATMENT Half life is 10-20 days clearance is decreased by 40% in the presence of MTX (+reduction of antihuman AB) registered for RA, JIA, Bechterew’s disease (ankylosing spondylitis), psoriasis and both IBDs,PsA, plaque psoriasis, Behcet disease, sarcoidosis, noninfectious uveitis. In RA they are mostly combined with MTX, but monotherapy is also possible. Side effects: risk of infections (tuberculosis, opportunistic infections, activation of latent viral hepatitis), infections site and infusion reactions, allergy

Answer 19

 Human AB  Use sc. once / month ANTI-TNFa TREATMENT s. Golimumab has not yet registered for CD Side effects: risk of infections (tuberculosis, opportunistic infections, activation of latent viral hepatitis), infections site and infusion reactions, allergy

Answer 20

``` -Humanized AB Fab fragment bound to Polyethylenglycol (Pegylated) -Use sc. once / 2 week or 1 month ANTI-TNFa TREATMENT ``` Certolizumab is only indicated for RA – it can have small difference in effect, because it does not activate complement system In RA they are mostly combined with MTX, but monotherapy is also possible Side effects: risk of infections (tuberculosis, opportunistic infections, activation of latent viral hepatitis), infections site and infusion reactions, allergy

Answer 21

IL-6-R antobody (soluble or membrane bound)  They block the receptor (not the cytokine itself) Inhibit B-cell activation, differentiation of naive CD4+ T cell  Th17 -systhesis of acute phase proteins ◦ Very efficient in monotherapy, without csDMARDs  Use: Tocilizumab is for RA and JIA, SysSclerosis, sarilumab is still for RA only., SJIA, PJIA,  Tocilizumab is given monthly iv., sarilumab iv. or sc. in 2 weeks half life is 11 days combination or monotherapy  Adverse effects: similar to TNFα inh., neutropenia, lipid level increase (LDL), thrombocytopenia, , infections (tuberculosis, fungal, viral), URespiratoryTI, headache, hypertension, anaphylaxis (fewer than 1%),

Answer 22

 Antibody against B-Lymphocyte-Stimulator-Protein (BLyS, BAFF). It inhibits the survival of autoreactive B-cells and the differentiation into plasmocytes. It normalizes low complement level in SLE.  Use: it is registered till now for SLE  SE: fever, leucocytopenia, migraine, arthralgy

Answer 23

``` fully human IgG It binds to the common p40 subunit of IL-12 and IL-23. IL-12 would activate the formation of Th1 (CD4+) and NK-cells, while IL-23 activates Th17 proinflammatory lymphocytes. bioavailability 57 % sc. elimination half life: 10-126 days monotherapy or combination with MTX ``` Use: it is used for psoriasis (Plaque Psoriasis and Arthritis Psoriatica) PsA and for CD. Adverse effects: Infections (UrespTI), maybe malignancy, reversible posterior leukoencephalopathy syndrome

Answer 24

anti IL-23 antibody IL-23 activated Th17-cells till now for Plaque Psoriasis registered

Answer 25

 THEY BLOCK THE PROINFLAMMATORY CYTOKINE IL-17 PRODUCED BY TH17 CELLS  USE: PSORIASIS (PLAQUE PSORIASIS AND ARTHRITIS PSORIATICA - SECUKINUMAB) , BECHTEREW’S DISEASE (SECUKINUMAB), THEY ARE INEFFECTIVE IN CD!  ADVERSE EFFECTS: INFECTIONS (RESPIRATORY), ALLERGY (RHINITIS)

Answer 26

ANTI IL-17R ANTIBODY  Registered for plaque psoriasis  Adverse effects : arthalgia, headache, tiredness, diarrhea, stomachache

Answer 27

 It is a long acting analogue of the endogenous IL-1R antagonist peptide inhibits the activation of neutrophils  Use: In RA it seems less effective than TNFα blockers. Otherwise it is indicated for cryopyrin-associated periodic Syndromes (CAPS)  It has similar side effects as TNFα blockers (milder). It mustn't be combine with them.  Daily sc. Administered

Answer 28

Anti IL-1β bilogicals Patients with CAPS have mutation on NLRP-3 gene. This mutation causes an excessive release of IL-1β in certain situations. It causes fever, exanthemas and arthralgia etc. Use: cryopyrin-associated periodic syndrome (CAPS), JIA, gout Adverse effects: headache, dizziness, weight gain, infections

Answer 29

Reslizumab  IT IS USED FOR SEVERE EOSINOPHILIC BRONCHIAL ASTHMA  ADVERSE EFF: CK ELEVATION, ALLERGIC REACTION

Answer 30

Benralizumab  IT IS USED FOR SEVERE EOSINOPHILIC BRONCHIAL ASTHMA  ADVERSE EFF: CK ELEVATION, ALLERGIC REACTION

Answer 31

ANti IL-5 AB  IT IS USED FOR SEVERE EOSINOPHILIC BRONCHIAL ASTHMA  ADVERSE EFF: CK ELEVATION, ALLERGIC REACTION

Answer 32

Anti IL-5-Receptor AB  IT IS USED FOR SEVERE EOSINOPHILIC BRONCHIAL ASTHMA  ADVERSE EFF: CK ELEVATION, ALLERGIC REACTION

Answer 33

Anti IL-4αR and IL-13R AB  It blocks also Th2 medaited immunoreaction. It was registered for eosinophylic asthma and for sever atopic dermatitis  AE: Local reactions, oral herpes, coniunctivitis, AB formation

Answer 34

Basiliximab (Daclizumab)

Answer 35

Rituximab, | Ocrelizumab

Answer 36

Alemtuzumab

Answer 37

Guselkumab, Tildrakizumab, Rizankizumab

Answer 38

Brodalumab

Answer 39

Rilonacept

Answer 40

CTLA-4/Fc fusionprotein  It blocks the binding of the costimulator CD28 protein to CD80/86. (It binds to CD80/86). CD80/86 – CTLA4 interaction is inhibitory on lymphocytes. preventing the activation of T-cells IV or sc. serum half life: 13-16 days Co-adminst. of corticoids. MTX or NSAIDs does not influence clearance equivalence to adalimumab can be used in combination with MTX or monotherapy  Use: RA, JIA (with uveitis), psoriatic arthritis, PJIA, (IBD; Sjörgensen Syndrom, SLE, DM1, psoriasis vulgaris)  Adverse effects: headache, infections, (neutralizing) AB production, concomitant use of biologics is not recommended (serious infection), tuberculosis and HBV screening, infusion related hypersensitivity reaction (including anaphylaxis; rare), possible increase in lymphoma

Answer 41

ipilimumab

Answer 42

Anti-PD-1 Antibody

Answer 43

Anti-CTLA-4 antibody

Answer 44

NATALIZUMAB integrins expressed on leukocytes except neutrophils inhibits the alpha4 mediated adhesion of leukocytes to their cognate receptor MS and Crohn´s disease should not be used with any of the anti-TNFa-drugs increses risk of progressive multifocal leukoencephalopathy (JC virus?) (Vedolizumab)

Answer 45

 It inhibits the docking and extravasation of T-cells trough α4β1 – VCAM-1 interaction in CNS and α4β7 Binds to the alpha4 subunit of both the alpha4ß1 (VCAM-1 binding is inhibited) and alpha4ß7 (MadCAM-1 binding is inhibited) integrins integrins expressed on leukocytes except neutrophils inhibits the alpha4 mediated adhesion of leukocytes to their cognate receptor MS and Crohn´s disease should not be used with any of the anti-TNFa-drugs increses risk of progressive multifocal leukoencephalopathy (JC virus?) – MadCAM-1 in GI Tract.  Use: It is used in MS (it not anymore used in CD)  Adverse effects: fever, nausea, infections. It can activate with ca. 1:1000 possibility polyomavirus JC (John Cunningham). This can lead to progressive multifocal leukoencephalopathia (PML). leukocyte adhesion is blocked

Answer 46

 It is selective to GI type α4β7 Integrin. ◦ Binds to the ß7 subunit of alpha4ß7 integrin (MadCAM-1 binding is inhibited) ◦ SE: infections (nasopharyngitis, bronchitis, influenza, sinusitis), headache, nausea, fever, fatigue, cough, joint pain Therefore it is useful only for CD, but it do not activates JC virus. like Natalizumab

Answer 47

Omalizumab

Answer 48

Antibody against Fcε part of IgE. It can reduce circulating IgE level up to 90% ``` Use: severe bronchial asthma, chronic urticaria (see in asthma chapter) ``` Adverse effects: allergy, local reactions

Answer 49

eculizumab

Answer 50

```  Antibody against complement factor C5  It is used for patients with paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome  Orphan drug ```

Answer 51

SULFASALAZINE ->(mesalazine) and sulphapyridin | olsalazine, balsalazide

Answer 52

 Sulphasalazin is cleaved in colon to 5-ASA (mesalazine) and to sulphapyridin) (Olsalazine and balsalazide are other prodrugs of 5-ASA.) Sulphapyridine is resorbed from GI tract and possibly it is active in RA. 5-ASA is not absorbed and it is important in IDB treatment. 1. 5-ASA induced PPARγ expression a) it inhibits the activation of NFκB and b) TLRs. 2. also blocks the function of cytokines IL-1, (IL-2,) IL-6, (IL-8, ), IL-12, TNFa 3. blocks COX and LOX 4. an antioxydant as well Mechanism of action of sulphapyridin is unknown Kinetics: 10-20% of suphasalazine is absorbed (without cleaving) and partially through urine and bile excreted. Sulphapyridin is metabolized in the liver. 5-ASA remains unabsorbed half life is: 6-17 hours Use: Suphasalazine is used in RA, ankylosing spondylitis (Bechterew’s disease), Juvenile chronic arthritis and in IBDs. Its effectivity in RA is relatively mild. The other 5-ASA derivatives are used for IBDs. In UC they are very effective, in CD their effectivity is questionable Adverse effects: sulphasalazine: nausea, vomiting, headache, rash (often), BM suppression, oligospermia. Other derivates: headache, nausea (rare), diarrhea, methemoglobinemia (rare), neurtopenia>thrombocytopenia, hemolytic anemia, dsDNA, pulmonary toxicity, drug induced lupus is rare, reversible infertility in men, does not affect fertility in women, microgranules, suppositories, enema -> Action is exerted loacally therefore early absorption must be avoided – either prodrugs or special formulations are used

Answer 53

Possible mech. of action: they increase the pH in lysosomes of macrophages, and hereby inhibit the catabolism and presentation of antigens. Moreover they block autophagy and formation of proinflammatory mediators.  Kinetics: They are well resorbed and they have extremely large volume of distribution because tissue binding. Half-life is long (up to 40 days). They are metabolized in liver.  Use: In RA they can be used in monotherapy only in very mild cases otherwise they can be combined with other DMARDs. In SLE and DLE they are more effective and first of choice drugs for less complicated cases. They can be used in Sjörgen’s syndrome as well.  Adverse effects: skin exanthemas, stomachache, nausea, vomiting, myopathy, nightmares, macula degeneration and cornea discoloration (ophthalmologic control is needed)

Answer 54

 The mechanism of action is unknown. It activates nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway. It reduces oxidative stress.  Use: orally administered for MS. Other fumaric acid esters are used for psoriasis.  Adverse effects: lymphocytopenia, flush

Answer 55

 Sphingosine 1-phosphate receptor modulator. S1PR controls the release of lymphocytes from lymph nodes and thymus and their penetration into CNS. S1PR is also expressed on neurons and influences neurodegeneration and gliosis.  Use: orally administered for MS, Siponimod as orphan drug registered for dermatomyositis and polymyositis  Adverse effects: headache, GI disorders, cardiac SE: AV block, QT prolongation  Ozanimod is in clinical trials for UC

Answer 56

 It is a standardized mix of polypeptides containing L-Alanin, L-glutamate, LLysine, L-Tyrosine – it is similar to myelin basic protein.  It competes with binding of MBP on MHC molecules and hereby antigen presentation. It induces GA specific regulatory Th2 cells and neurotrophic factors.  It is used sc. for MS  Adverse effects: skin reactions on injection site, flush, diarrhea

Answer 57

 It inhibits angiogenesis, TNFα secretion and activates IL-10 secretion. Blocks neutrophil functions as well.  Mainly used for multiplex myeloma and for erythema nodosum leprosum treatment. Off label sometimes used for SLE.

Answer 58

 cPDE4 Inhibitors. cAMP – PKA pathway is anti-inflammatoric.  Roflumilast used for COPD, Apremilast for psoriatic arthritis (see COPD) and plaque psoriasis registered  AE: nausea, diarrhea, headache, respiratory infection)

Answer 59

 Type I Interferons (α subtypes and β Inf) are part of the innate immune system. They use common receptors, and could have also immunosuppressive functions.  Use: Inf-α subtypes are used for viral infections and for tumor therapy. Inf-β-1a and 1b are used in remitting relapsing MS (3 times a week sc.) Inf-β-1a is also available in pegylated form and given in every two weeks.  Adverse effects: flu like symptoms (fever, tiredness, muscle pain etc.), suppression of BM, GI disorders, disturbance of liver and kidney function, CNS problems, etc.  Inf-γ is used as an immune stimulant in chronic granulomatosis.

immunopharmacology Flashcards

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