Introduction to Joint DIsease Flashcards

Question

How shoudl NSADs be involved in the treatment of gout?

Answer 1

withing the first 24 hours indomethacin and naproxen NOT ASPIRIN but remember that there are contraindications to NSAID (GI, platelets, renal, hypersensitivity)

Answer 2

Salicylic acid specific effect * dose dependent effect: _low doses of aspirin decrease uric acid excretion_ bc there is a small secretory component in the neprhon for urate and this secretory portion is sensitive to low doses of salicylates. meaning they stop secretion. this leads to a _build up of salicylates_ * large doses actually incerase excretion, but we still just don't give aspriing in gout due to the low dose influence on uric acid secretion

Answer 3

symptomatic relief in patients that can't take NSAID, short term use due to adverse effects that occur with extended use

Answer 4

* **therapeutic use:** Cochicine is used for acute gout attacks within hours or prophylactically in pts. with chronic gout * **MOA:** _anti-mitotic. binds to microtubules in inflammatory cell (PMNs) and inhibits neutrophil activation and migration_ by arresting cells division in G1 by interferring with microtubules. if inflammatory cells can't respond then there is not as much inflammation! * **pharmacokinetics:** oral, rapid absorption but variable, deposits in tissue stores/forms complex w tubulin (large volume of distribution), * metabolized by :CYP450s, substrate for P-glycoprotein which is a transmembrane ptoein that eliminates drugs) so think about drug drug interactiosn w colchcine

Answer 5

a pump (transmembrane protein) that eliminates drugs

Answer 6

* **adverse efffects:** significant! narrow therapeutic toxicity window. * **GI** (nausea, vominiting, diarrhes, abdominal pain) * usually a latent period before symptoms but it effects the rapid proliferatin cells of the GI * these GREATLY limit the use of the drug * **contraindications** * hepatic or renal disease (decrease dose or less frequent doses), elderly patients, * _especially if they are tkainf a CYP3A4 or P-gp inhibitor bc it would increase the concentration of colchicine_

Answer 7

* abstain from alcohol * weight loss * discontinue medicines that impair uric acid excretion like aspirin or thiazide diuretics

Answer 8

allopurinol febuxostat probenecid pegloticase

Answer 9

* **therapeutic use:** prevention of primary hyperurecemia of chronic gout * severe forms of gouty nephrology, tophaceous deposits, renal urate stones (also management of hyperuricemias associated w chemo/radiation) * **Mechanism of action:** blocks xanthine oxidase (last stepish in the uric acid production pathway) * **pharmacokinetics:** metabolized to an active compoud(oxypurinol) so allopurinol's half life is only 1-2 hours, but once it is metabolized it is metabolized to oxypurinol whose half life is 18-30 hours, ad this is still active in prevention of uric acid synthesis * **adverse effect:** hypersensitivity, acute gout attack bc mobilizes tissue stores of uric acid so you would give this drug w cochicine or NSAID

Answer 10

* Febuxostat is a newer drug and a non-purine **xanthine oxidase inhibitor** * more potent * more effective than allopurinol in the subset of patients with impaired renal function * adverse effects similar to allopurinol * the incidence of CV side effects was higher with Allopurinol than febuxostat

Answer 11

(gout) * recombinant form of urate-oxidase enzyme (uricase) which is normally absent in humans and conveerts uric acid to allantoin which is an inactive water soluble metabolite * there is a PEGylates glycol covalently linked to the moelcule * adverse effects: infusion site rxns, gout flare (so need prophylaxis for acute flares) immune response (directed at PEG portion of molecule)

Answer 12

* **Use:** a uricosuric agent (monotherapy). it is a drug that increases the rate of excretion of uric acid * **MOA:** increase uric acid excretion by competing with the renal tubular acid transporter so that less urate is reabsorbed into the urine (OAT aka URAT1)

Answer 13

* some GI effects, ineffective in pts w renal insufficiency * contraindicated in patient with uric acid kidney stones * use when don't respond to xanthine oxidase inhibitor (like allopurinol)

Answer 14

* allopurinol or febuxostat: inhibit the metabolism of azathiorine and mercaptopurine so increased toxicity with these drugs * cochicine: susceptible to inhibition of CYP3A4 metabolism and P-gp transport * Probenecid: interference with renal excretion of drugs that undergo active tubular secretion, especially weak acids

Answer 15

* inhibitory: * XO inhibitors: Allopurinol (oxypurinol), febuxostat * NASIDS, colchicine, steroids * stimulatory: * uricosurics: probenecid * uricases: pegloticase

Answer 16

* inflmmatory symmetric chronic polyarthritis * immunological disease (both T and B cells) * genetic predisposition (HLA-DR4, HLA-DR1) * 1st degree relatives of an RA patient at 1.5 fold higher risk of developing the disease * WWP: 1%, women over men

Answer 17

* dendritic (antigen-presenting) cells phagocytose anitgens and present them to T cells * activated T cells stimulate the production of B and T cells * B cells produce plasma cells that form rheumatoid antibodies * Helper T cells activate macrophages and cytotoxic T cells * Togteher, T cells, macrophages, and cytotoxic T cells produce cytoxic cytokines (TNFa, IL1, IL6 and others) and prostaglandins that cause joint inflammation, synovial proliferation and bone and caritlage destruction

Answer 18

* gradual onset of joint pain, swelling and inflammation present for greater than 6 weeks * symmetrical in nture and often involving small joints (MCP, PIP, but NOT DIP) * morning stiffness lasting longer than 1 hour * elevated markers of inflamamtion and abnormal serology

Answer 19

* swan neck deformity * boutiniere deformity * RA nodules * \*\*usually see ulnar deviation and erosion

Answer 20

no! there are several extra-articular manifestations rheumatoid vasculitis interstitial lung disease premature coronary artery disease secondary sjorgens syndrome feltys syndrome (big spleen. low WBC count)

Answer 21

* a covering that grows and covers up the cartilgae and the synvoium within it are inflammatory cells there are aslo inflammatory cells in the snovial fluid * papillary strucutres composed of synovial hyperplasia, lymphoid infiltrates, and fibrin

Answer 22

* chronic papillary synovitis (finger-like projections) * **chronic inflammation of the synovium**: CD4+ T cells, plasms cells and macrophages, giant cells * frequently forming lympohoid follicles * accompanied by **synovial cell hyperplasia** * results in papillary pattern on the surface of the synovium * PMNs and fibrin on joint surfaces in acute phase * Hyperplastic inflammed synovium extends over the articular surface forming a pannus which fills the joint space * Overtime articular cartilag is destroyed * increased osteoclast activity in underlying bone causing bone to be eroded (destroyed) * end result may be joint fusion (ankylosis) due to fibrosisossification * Osteophytes and new bone formation are not prominent (unlike osteoarthritis)

Answer 23

* develop most commonly on skin (subcutaneous) in areas exposed to pressure (extensor surface of forearm and elbow) * less than 25% (severe disease) * less commonly in viscera * grossly: non-tender, firm, oval.round * microscopically: **central zone of fibrinoid necrosis** surrounded by rim of epithelail histocytes and then lymphocytes and plasma cells * causes of nodules: **necrosis secondary to vascular damage** possibly secondary to vasculitis (inflammation of the vessel walls) associated with RA

Answer 24

relieve pain, reduce inflammation, slow down or stop joint dmage, imrove a person's sense of well being adn ability to function

Answer 25

no effect on progression of disease, only relieves symptoms of pain. be careful about ulcers!!

Answer 26

class of drugs that include monoclonal antibodies, receptor analogues, and small molecules that are involved in modiying the disease process!

Answer 27

the half-life is 21 days for human mAbs. Long half-life=infrequent administration!! this is important because a lot of these drugs are administered parenterally (subQ 24-95% bioavailable, intramuscular 24-95%, IV 100%) they are distributed extracellularyl and don't cross the BBB

Answer 28

* generally safe and well tolerated * immunogenicity: generation of endogenous antibodies against the therapeutic ntibodies * **neutalize therapeutic antibodies**, or cause hypersensitivity reactions * **Increased risk of serious infections** * bacterial (opportunistic-due to imunosuppresion) and TB (screen for latent TB before beginnin treatment bc of increased risk of reactivation of latent TB)

Answer 29

* TI: moderate to severe RA, juvenile RA, early stage RA * MOA: inhibits the ability of TNF-a to bind to its receptor (inhibits solble form of TNFa) * long half-life * adverse effects: injection site reactions or infections

Answer 30

* TI: active moderate to severe RA, junvenile idiopathic arthritis, alone or in combo with methotrexate * MOA: binds to soluble and transmembrane forms of TNFa to prevent binding of TNFa to its receptor (remember etanercept was just the soluble form) * long half-life * adverse effects: injection site recations, infections

Answer 31

adalimumab- bind m-TNF and s-TNF and induce apoptosis of the expressing cells of TNF (ones that make it) Etanercept- only s-TNF

Answer 32

* TI: adult patients with moderately to severly active RA who have had an inadequate response to one or more _TNF agents_ * MOA: binds to soluble and membrane bound Il-6 receptors and inhibits Il-6 mediated signaling via these receptors (remember Il-6 activates T cells, B cells, macrophages, and osteocalsts and mediator of acute phase resonse) * long half-life * adverse effects: injection site reactions, increased risk of infections, alterations in lipid profile (increases in total cholesterol, triglycerides, LDL, and/or HDL

Answer 33

* TI: treatment of moderately to severely active RA in patients who have had an inadequate response or intolerance to _methotrexate_ * MOA: inhibits Janus kinase (JAK) enzymes which are intracellular enzymes involved in stimulating immune function * oral administration * adverse: * increase risk of infections, alteration in lipid profiel (increases in total cholesterol, triglycerides, LDL and/or HFL)

Answer 34

* TI: moderately to severely active RA (in combo w methrotrexate) in adult patients with inadequate response to one or more TNF antagonists * MOA: **B cell-depleting monocolonal anti-CD20 antibody** * ****CDC, ADCC * long half-life * adverse: injection site reactions, increased risk of infections

Answer 35

\*\*RA\*\* * **inhibiting the binding to CD28** therefore **preventing the activation of T cells** (interfing with co-stimulation) Abatacept contains CTLA-4 that binds CD80/86 so CD28 can't! (fusion protein CTLA-4=endogenous ligand for CD28) * long half-life * adverse effect: injection sit ereactions, infections * TI: moderately to severely active RA in adults inadequate response to one or more DMARDs or TNF inhibitors

Answer 36

* **Abatacept:** blocks co-stimulation of T cells * **Methotrexate and leflunomide:** inhibit the proliferation and activity of B cells and T cells * **Etanercept, infliximab, adalimumab, golimumab, and certolizumab:** inactivate TNF a * **Anakinra:** block the activation of I-L-1, * **Tocilizumab:** inactivates IL-6 * **glucocorticoids:** inhibit T cell activation and IL-2 production by regulation of gene transcription, and inhibit formation of prostaglandins * **NSAIDs:** inhibit formation of prostaglandins

Answer 37

Methotrexate, leflunomide, hydroxychloroquine

Answer 38

* it is a structural analog to folic acid. it inhibits the folate pathway (therefore purine and pyrimidine synthesis). works by blocking dihydrofolate reducatse * accumulation of adensoine has anti-inflammatory effects

Answer 39

* long-term, low-dose therapy oral, IM or SubQ * common toxicities are GI (nausea), stomatitis or soreness of the mouth, rash on extremities, CNS (headache fatigue) and hemtologic abnormalities

Answer 40

* GOAL=remission * Non-biologic DMARD: Methotrexate * alternative include other non-biologics like leflunomide or sulfasalazine or the DMARD Biologic, TNFa inhibitors * symptomatic reliefs with NSAIDs

Answer 41

* progressive, degenerative joint disroder caused by gradual loss of cartilage which results in bony spurs at margins joints and subchondral cysts * most common cause of arthritis in adults * risk fctors * female gebder * advanced age * genetic predisposition * obesity * diabetes * trauma

Answer 42

* Non-inflammatory joint pain * worse w activity * minutes of morning stiffness (remember RA was an hour) * brief stiffess after prolonged immobility ("gelling") * associated with "crunching" (loud joint)

Answer 43

* Osteo: * fusiform swelling of joint * Herden's nodes (bony enlargement of DIP joints. remember RA spares DIP) * RA: * Boutonniere deformity of thumb * ulnar deviation of metacarophalngeal joints * swan nech deformities

Answer 44

* primarily based on joint distribution, character of pain, and exam findings * blood tests not helpful * X-rays not required (controversial) * synovial fluid aspiration may rule out other types of arthritis (non-inflamm aka osteo synovial fluid the WBC count would be less than 2000, whereas inflamm like RA WBC would be greater than 2000)

Answer 45

imbalance in cytokine and growth factor activity resulting in matrix loss and degradation (breakdown of normal physiologic process)

Answer 46

* superficial layers of cartilage are destroyed fibrilation and crackling of the cartilage matrix * limited chondrocyte proliferation and new matrix formation

Answer 47

* **absence of articular cartilage**; polished appearance of exposed bone (eburnation) * **subchondral sclerosis**: more dense bone develops underneath areas where cartilage is gone * **subchondral cyst**: formed by break in cartilage; this allows synovial fluid to be forced into subchondral space, forming fibrous walled cyst * **osteophyte formation**: bony outgrowth develops at margins of articular surface in characteristic locations fo specific joints; results in increased joint size * hip joint: all around entire joint margin, typically flat ostephyte on medial surfac extending to fovea * distal interphalangeal joint: Heberden nodes * proximal interphalangeal joint: Bouchard nodes

Answer 48

* weight loss, exercise, physical therapy * intra-articular therapies, corticosteroid, hyaluronans * topical therapies: capsaicin, salicylates, menthol * systemic: acetaminophen, duloxetine, NSAIDs

Answer 49

* use: OTC temporary treatment of pain associated w muscles and joints due to backache, strains, sprains, bruises, cramps, arthritis * MOA: agnosite for the TRPV1 receptor (transmembrane receptor ion-channel) * induces release of substance P (mediator from pain impulses from the periphery to the CNS) after repeated application, capsaicin depletes the neuron of substance P and prevents reaccumulation * adverse: local transient application sit reations, pain and erythmeia

Answer 50

* pain signals detced by nociceptors in periphery and carried to the dorsal horn or the spinal cord * nociceptors synapse with second-order neurons and carry the signal up the spinal cord * projection neurons relay pain signals to the brainstem. signals propagated to different areas of the brain. both facilitating and inhibtory descedning pathways (black arrows) modulate pain transmission. Descending inhibitory pathways release NE and 5-HT. SNRISs target desceding inhibitory athways

Answer 51

use: FDA approved from chronic musculoskeletal pain MOA: centrally acting oral analgesic, Serotonin-norepinephrine reuptake inhibitors (SNRI) lower dose adn faster acting pain relief effect than anti-depressant effect side effects: nausea, dry mouth, constipation,

Answer 52

* Glucosamine Sulfate * aminosaccharide * MOA principal substrate in the biosynthesis of proteoglycan, which is essential for maintaining cartilage integrity **(helps w proteoglycan synthesis which maintains cartilage integrity)** * Chondroitin Sulfate * glycosaminoglycan * MOA: * maintains viscosity in joints * stimulate cartilage repair mechanisms, * inhibit enzymes that break down cartilage

Answer 53

dietary supplements effectiveness of these remains to be established. regulated as food

Answer 54

* polysaccharide composed of glucosamine and glucuronic acid (exists in normal synovial fluid) * MOA: inhibiting inflammatory mediators, decreasing cartilage degradation, promoting cartilage matrix synthesis * Yse: approved for treating OA of knee, ppl who can't take NSAIDS, doesnt slow progression of OA * injections 1 daily for 3 weeks * adverse effects: joint inflammation, small risk of infection

Answer 55

no high quality evidence that opioids improve function more than nonopioid analgesics

Answer 56

1. comfort: 1. NSAIDS, prednisone 2. Disease modfying agent ("traditional" DMARD) 1. methotrexate (1st line) 2. sulfasalazine 3. leflunomide 4. hydroxychloroquine 3. Pending response add biologic 1. TNFa inhibitor (adalimumab, etanercept) 2. abatacept (blcoking the T cell-costimulation) 3. TOcilizumab (Il-6 inhibitor) 4. Tofactinib (Jak-kinase inhibitor) 5. Rituximab

Introduction to Joint DIsease Flashcards

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