Term
| What is the first choice to Tx RA? |
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Definition
| Methotrexate. NB that its used in a much lower dose then in chemo and that its given once weekly |
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Term
| How does methotrexate work? |
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Definition
| Its a competitive inhibitor of AICAR transformylase which catalyzes the penultimate and final steps in de novo purine biosyn -> IMP - -> AMP or GMP; thus inhibition of this enzyme will result in more adenosine, which is a powerful anti-inflammatory mediator by acting on A2b Rs -> suppresses NF-kappaB activation induced by TNF and other inflammatory stimuli |
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Term
| Which pyramidine may also be affected by the methotrexate-induced NF-kappaB suppression? |
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Definition
| The thymidylate synthase pathway |
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Term
| How can methotrexate toxicity be reduced? |
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Definition
| By giving leucovorin 24 hrs after each wk at the expense of efficacy; alternatively daily use of folate can have the same effect. |
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Term
| What are some of the A/Es of methotrexate use? |
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Definition
| Nausea, mucosal ulcers, dose-related hepatotoxicity thus checking every 5 yrs for cirrhosis, rare hypersensitivity lung rxn & pseudolymphomatous rxn |
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Term
| Can methotrexate be used in preg? |
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Definition
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Term
| What are the Cytotoxic agents? |
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Definition
| Alkylating agents (Chlorambucil & Cyclophosphamide); antimetabolites (Azathioprine); other (Leflunomide, Mycophenolate) |
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Term
| What is Chlorambucil’s metabolite? |
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Definition
| Phenylacetic acid mustard, which crosslinks DNA |
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Term
| What are the A/Es of Chlorambucil? |
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Definition
| Dose-related BM suppression, infertility, RR of leukemia increased by 10Xs |
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Term
| What is Cyclophosphamide’s metabolite? |
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Definition
| Phosphoramide mustard, which also crosslinks DNA. It suppress T and B cell function by 35% |
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Term
| What is Cyclophosphamide used for? |
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Definition
| Orally used for Tx-ing RA (but not when given IV), also Txs SLE and other rheumatic dzs |
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Term
| What are some of the A/Es of Cyclophosphamide? |
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Definition
| Dose-limited infertility in both sexes, BM suppression, hemorrhagic cystitis & rarely bladder CA. NB that Acrolein, one of the metabolites is probably responsible for the urinary toxicities |
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Term
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Definition
| Its a purine antimetabolite, which is an imidazolyl derivative. Its metabolised to 6-mercaptopurine which inturn is metabolised further to inhibt de novo purine synthesis -> T & B cell function suppression |
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Term
| What effect does allopurinol have on Azathioprine metabolism? |
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Definition
| Xanthine oxidase splits much of the active material into 6-thiouric acid to be excreted in urine, thus pts on allopurinol for control of hyperuricemia shud dose reduce to 1/4 - 1/3. |
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Term
| What are some of the A/Es of Azathioprine? |
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Definition
| BM suppression, GI disturbances, some increase in infections and malignancies |
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Term
| Which Rx do u know of that leads to decreased UMP? |
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Definition
| Leflunomide is rapidly metabolised to A77-1726, which inhibits dihydroorotate dehydrogenase -> decreased de novo ribonucleotide synthesis - -> lower UMP levels. This then results in the translocation of p53 to the nucleus. P53 is a sensor molecule and when activated stimulates cell arrest at G1 phase. Most affected are the activated lymphocytes which depend on de novo synthesis of pyrimidine because their need is increased eightfold |
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Term
| How can Leflunomide help pts who don’t respond to methotrexate? |
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Definition
| Its apart of a combination therapy |
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Term
| What are the A/Es of Leflunomide? |
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Definition
| Diarrhea and elevation of liver enzymes |
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Term
| Which Rx do u know that inhibits guanosine formation? |
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Definition
| Mycophenolate Mofetil which is a prodrug for mycopjenolic acid (MPA). NB that MPA is an inhibitor of inosine monophosphate dehydrogenase (IMPDH), the rate-limiting enzyme in the formation of guanosine |
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Term
| What is IMPDH needed for? |
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Definition
| The de novo synthesis and not the salvage pathway for G thus affecting lymphocytes. NB that of the two isoforms, type I and II, MPA goes after II, which is mainly in the lymphocytes |
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Term
| What is the name of the Immunophilin ligands? |
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Definition
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Term
| What Rx do u know of that is derived from the fungus Beauveria nivea? |
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Definition
| Cyclosporine, a cyclic polypeptide of 11 a.as |
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Term
| What is cyclosporine used for? |
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Definition
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Term
| How does Cyclosporine work? |
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Definition
| Cyclosporine inhibits antigen-triggered signal transduction in T lymphocyte lymphokines like IL-2 and also expression of antiapoptotic proteins. Cyclosporine forms a complex with cyclophilin (a member of an intracellular protein called immunophilin). This complex can now bind to and inhibit calcineurin, a phosphatase thats need for the activation of T-cell specific transcription factor. This transcription factor, NFAT (Nuclear factor of activated T lymphocytes) is required for the induction of a few cytokines like IL-2, T-cell growth and differentiation factor. |
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Term
| What are some of the A/Es of using Cyclosporine? |
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Definition
| Nephrotoxicity, tremor, hypertension, hyperglycemia, hyperlipidemia, osteoporosis, hirsutism, gum hyperplasia. NB that there is very lil BM toxicity |
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Term
| What is the major toxicity that indicates the cessation of Cyclosporine? |
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Definition
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Term
| What is the Antimalarial drug? |
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Definition
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Term
| What is the anti-inflammatory mechanism with Hydroxychloroqunine? |
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Definition
| Not clear so there is a shit load of ideas... |
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Term
| How long do Hydroxychloroqunine need to be effective? |
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Definition
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Term
| What other Dz does Hydroxychloroqunine Tx? |
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Definition
| Mild RA & is well tolerated |
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Term
| What other Rx can Hydroxychloroqunine be mixed with? |
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Definition
| Methotrexate & sulfasalazine |
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Term
| What are some of the A/Es of Hydroxychloroqunine use? |
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Definition
| Corneal deposition (reversible with stopping Rx), ophthalmologic monitoring every 6-12 mos |
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Term
| Which Rx do you know that has a diazo bond? |
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Definition
| Sulfasalazine which consists of sulfapyridine and 5-aminosalicylic acid (5-ASA) linked by a diazo bond. It is metabolized by bacteria into its moieties, which have some anti-inflammatory axn and inhibit immune reactivity. NB that 5-ASA is not that important in RA but is in UC. |
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Term
| What is Sulfasalazine used for? |
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Definition
| Juvenile arthritis & ankylosing spondylitis |
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Term
| What are the A/Es of Sulfasalazine use |
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Definition
| Nausea, anorexia and rash are common. Serious rxns like hepatitis, leucopenia & agranulocytosis are rare. NB that a SLE-like syndrome has been reported. Also hemolysis occurs in G6PD deficient pts. |
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Term
| Is Sulfasalazine safe for preg pts? |
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Definition
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Term
| What are the two formulation of Gold compounds? |
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Definition
| Gold sodium thiomalate (IM), Auranofin (orally) |
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Term
| How do Gold compounds work? |
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Definition
| Gold salts are taken up by macrophages and suppress phagocytosis and lysosomal enzyme activity -. Retards bone & articular destruction |
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Term
| What are some of the A/Es of Gold compounds? |
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Definition
| Stomatitis, rash, proteinuria, and less commonly leucopenia & thrombocytopenia. |
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Term
| Can Gold Tx be used in preg? |
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Definition
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Term
| What are the Anti-cytokine drugs? |
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Definition
| Anti-TNF drugs (Adalimumab, Infliximab, Etanercept); Anti-interleukin drugs (Anakinra) |
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Term
| What cytokines are involved in RA? |
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Definition
| IL-1 & TNF-alpha (more so and binds to R1 & 2) |
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Term
| What are the three anti-TNF Rxs? |
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Definition
| Adalimumab (fully human IgG1 complexes w/ soluble TNF to prevent its axn w/ p55 & p75 cell surface Rs => down-regulating MAC & T-cell function), Infliximab (IV chimeric Ab similar to adalimumab), Etanercept (a slow absorbing injection recombinant fusion protein that consist of two soluble TNF p75 R moieties linked to Fc portion of human IgG1, not only does it bind TNF but also inhibits lymphotoxin-alpha) |
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Term
| What 3 other Dzs can Infliximab be used for? |
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Definition
| Ankylosing spondylitis, CD, psoriatic arthritis |
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Term
| What is the most common A/E reported when using Infliximab + methotrexate? |
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Definition
| URTI, other common ones include: nausea, headaches, sinusitis, rash and cough. NB that methotrexate is used in the background to reduce HACA (human antichimeric Abs). Furthermore although there are anti-nuclear Abs and anti-ds DNA Abs, Rx-induced SLE is rare but even more its mild and reversible |
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Term
| Do anti-etanercept abs presage toxicity? |
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Definition
| Appear sporadically, and nope, nor do they affect efficacy; although markers are present there are no lupus-like rxns |
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Term
| Do anti-etanercept abs presage toxicity? |
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Definition
| Appear sporadically, and nope, nor do they affect efficacy; although markers are present there are no lupus-like rxns |
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Term
| What is the only anti-IL Rx? |
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Definition
| Anakinra, a recombinant non glycosolated version of human IL-1 R antagonist. It has 153 a.as which is one more methionine residue on the amino terminus then native IL-1RA |
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Term
| What is the MOA of glucocorticoids? |
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Definition
| They inhibit phospholipase A2 thus no liberation of arachidonic acid and it ALSO inhibits expression of COX-2. NB that its effects on RA is prompt and dramatic but because of its long term A/Es is only used in short-term |
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Term
| What are the A/Es of using glucocorticoids? |
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Definition
| Osteoporosis, weight gain, fluid retention, cataract, poor wound healing, gastric ulcers, GI bleeding, hyperglycemia, hypertension, adrenal suppression & increased risk of infection |
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Term
| Comment on combination of DMARDs? |
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Definition
| Combos revolve around methotrexate. Leflunomide + methotrexate increases risk of hepatotoxicity thus monitor closely. Combo of anakinra + TNF inhibitors increases the risk of neutropenia and thus infection and hence shud not be used routinely |
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