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29 Cards in this Set
- Front
- Back
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what is osteoporosis
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- low bone mass, microarchitectural disruption
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List drugs used to treat osteoporosis [3]
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1. Bisphosphonate
2. Teriparatide 3. Denosumab |
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Describe bisphosphonate:
- examples [4] - mech of action [2] - pharmacokinetics [2] - ADR [3] - Precautions [4] - what is the FDA-issued safety alert [2] |
alendronate, risedronate, ibandronate, zoledronate (IV)
Antiresorptive/anticatabolic agents - bind to bone matrix to ↑bone mineral density - ↑osteoclast apoptosis, inhibit osteoclast function Pharmacokinetics - poorly absorbed from intestine, limited bioavailability - w. full glass of water after overnight fast, at least 30 mins before breakfast ADR - GI irritation - osteonecrosis of jaw - atypical femoral fractures [chronic use] Precaution: - growing children + women of child-bearing age - upper GI disease - calcium supplement or med w. divalent cations (iron) - renal insufficiency FDA-Issued safety alert - accumulated by bone, released slowly - ↑risk of atypical femoral fractures if >5 yrs [needs drug holiday] |
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What is teriparatide (parathyroid hormone 1-34)
- MoA and Pharmacokinetic - ADR [3] + black box - contraindication [4] - therapeutic strategy [2] |
Anabolic agent
- active PTH receptor in bone, ↑bone formation - subcutaneous injuection (once daily, thigh/abdomen) ADR - injection site pain, headache - nausea, dizzy - leg cramp *Black box* ↑osteosarcoma risk! Limit tx to 2 years, only in px refractory to bisphosphonate/high risk fracture Contra - open epiphyses - bone mets - prior skeletal radiation - elevated alkaline phosphatase level Therapeutic; *restore bone strength, *prevent fractures |
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Denosumab
- MoA [2] - pharmacokinetic - potential adverse effects [4] - contraindication [2] |
Human monoclonal ab binds to receptor:
- activate RANKL (nuclear factor-kB ligand) on surface of precursor & mature osteoclast - block osteoclast formation & activation - subcutaenously once every 6 months ADR: - hypocalcemia - allergic reaction - infection - jaw bone necrosis Contra: - low blood calcium - planning to get preg/is preg |
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what is the action of RANKL (NF-kB ligand) ?
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Acts on RANK (receptor activator of nuclear factor kB)
- promotes osteoclast formation - resorption of bone matrix |
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Describe DMARDs [3] how do they work? how long? what used with?
- MoA |
Disease modifying anti-rheumatic drugs
- retard progress of RA's bone & cartilage damage - act slowly: 2 weeks-6 months, - used in conjuction w. anti-inflamm drugs MoA - non-biological small molecules: unclear, and long-term efficacy is controversial - affect more basic inflamm mechanisms than glucocorticoids or NSAID |
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Give example of DMARDS, and one example of each type
1. [5] 2. [5] |
1. Non-biological
- Cytotoxic agents (methotrexate, lefulnomide, cyclophosphamide, azathioprine) - Sulfasalazine - Antimalarial (chloroquine, hydroxychloroquine) - Immunosuppressant (cyclosporine, mycophenolate mofetil) - Gold (aurothiomalate, auranofin) 2. Biological - TNF-a blocking agent [etanercept, infliximab, adlimumab, golimumab, certolizumab) - T-cell co-stimulation modulator [abatacept] - B-cell cytotoxic agent [rituximab] - IL-1 receptor antagonist [anikinra] - IL-6 receptor antagonist [tocilizumab] |
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what is DMARD triple therapy ?
- what should NOT used in combination with TNF inhibitor? [3] why? |
<Non-biological>
- methotrexate [Cytotoxic agent] - sulfasalazine - hydroxychloroquine [antamalarial drugs] <Biological> - T cell co-stimulation modulator, - B-cell cytotoxic agent, - IL-1 receptor antagonist, ↑risk of infection so NOT recommended |
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Methotrexate -
- contraindicated - Low dose [3] - ADR [5] |
- folate analogue (antifolate)
- Pregnancy because cytotoxic agent Tx RA in low doses 1. suppress inflamm function of N, M, L, dendritic cell *inhibit AICAR transformylase + thymidylate, ↑extracellular adenosine *inhibito dihydrofolate reductase 2. inhibit proliferation and stim. apoptosis of immune-inflamm cell 3. inhibit proinflammatory cytokines ADR: - GI disturbance, mucosal ulcer - hypersensitivity (MTX lung) - hematologic toxicity - dose-related hepatotoxicity (monitor liver function) - reduced by concomitant use of leucovorin/folate AICAR stands for (aminoimidazolecarboxamide ribonucleotide) |
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Leflunomide
- describe what it is - active metabolite - ADR [5] - contra - long half-life |
pyrimidine analog and cytotoxic agent
Active metabolite: A77-1726 - inhibit dihydroorotate dehydrogenase ↓T cell, ↓B cell proliferation, ↓TNFa-dependent NF-kB activation ADR: - GI disturbance - elevate liver enzymes - rash, allergic reaction - alopecia, hair-thinning - potential teratogenic effects Contra - pregnancy and breast-feeding - elimination enhanced by cholestyramine |
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Sulfasalazine (salicylate)
- MoA [2] - ADR [5] - clinical use |
MoA
- inhibit release of inflammatory mediators - module immune response (suppress T-cell receptor, inhibit B-cell proliferation) ADR: - GI distrubance - allergy (sulfa med: sulfonamide, aspirin) - hematologic toxicity, hemolytic anemia (G6PD def px) - pneumonitis, hepatitis - male infertility [reversible] used in triple tx with MTX & hydroxychloroquine |
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Hydroxychloroquine
- MoA [3] - ADR [3] - clinical use [3] |
quinolone ~ antimalarial chemo
MoA - suppress T-cell response - ↓leukocyte chemotaxis - stabilise lysosomal enzymes ADR - GI disturbance - rash - high dose: ocular toxicity - reserved for mild disease (limited efficacy) - used with MTX or in triple tx - rel. safe in pregnancy |
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Cyclosporine
- MoA [3] - ADR [3] - interactions [2] |
immunosuppressant: calcineurin inhibitor
Inhibit gene transcription 1.*↓IL-1 production, IL-2 receptor 2.*inhibit macrophage-T-cell interaction 3.*↓T-cell responsiveness ADR *renal dysfunction and hypertension *hyperlipidemia, gingival hyperplasia, hirsutism *hematologic toxicity 3. Drug interaction *CYP3A inhibitor ↑plasma cyclosporine conc. [diltiazem, glucocorticoid, allopurinol, grapefruit juice] *drug causing renal dysfunction ↑nephrotoxicity risk [NSAID] |
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Cyclophosphamide
- MoA - ADR [7] - Clinical use [3] |
MoA: cytotoxic agent, alkylating agent, deplete B & T cell
ADR - bone marrow suppression - GI disturbance - cystitis - hematopoietic malignacy - toxicity (pulmonary, renal, hepatic, cardiac) - sterility - teratogenic [contraindicated in preg + breastfeed] Clinical - narrow TI - for severe form of rheumatic disease - avoid long-term admin: switch to less toxic after 3-6 months |
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Azathioprine:
MoA ADR [4] Contra [1] drug interactions [2] |
Purine analog, cytotoxic agent
MoA: active metabolite ~ 6-thioquanine [by action of TPMT: thiopurine methyltransferase] *↓B-cell, ↓T-cell, ↓immunoglobulin, ↓IL-2 ADR: - bone marrow suppression - GI disturbance - hepatitis, pancreatitis - hypersensitivity Contra: low TPMT patients, ↑myelosuppression risk Drug interaction - sulfasalazine (because ↓TPMT activity) - allopurinol (because ↓elimination azathioprine) |
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TNFa blocking agents
- list them [4]: *what type of antibody *actions *administration - ADR [4] |
1. Adalimumab and golimumab
- human anti-TNF monoclonal antibody: - complex with soluble TNFa to down-regulate macrophage + T-cell function - subcutaenous (t1/2 10-20 days. clearance ↓by MTX) 2. Infliximab - chimeric (25% mouse, 75% human) IgG1 anti-TNF monoclonal ab - complex w. soluble & membrane-bound TNFa - IV infusion over 2-3 hrs 3. Etanercept - recombinant fusion (2 soluble TNF p75 receptor moieties linked to Fc portion of human IgG1) - bind TNFa, inhibit lymphotixn a - subcutaneous (t1/2 4.5 days) 4. Certolizumab - recombinant, humanized ab Fab fragment conjugated to polyethylene glycol. specificity for human TNFa - binds soluble & membrane-bound TNFa - subcutaneous (t1/2 14 days) ADR - ↑lymphoma risk - ↑infection risk - injection site (erythema, pruritus, pain, swelling) - infusion reaction (fever, chill, uritcaria, cardiopulmonary sx) |
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IL-1 receptor antagonist
- give example: what it is, action, administration - ADR [2] |
Anakinra:
- human recombinant IL-1 receptor antagonist - block biological activity of IL-1 - subcutaneous admin, once daily aDR - injection site reaction - ↑infection risk (greater risk w. TNF inhibitors so combination is NOT recommended |
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IL-6 receptor antagonist
- give example: what it is, action, administration - ADR [4] |
Tocilizumab
- humanized ab binding to soluble & membrane-bound IL-6 receptor - lock biological activity of IL-6 - IV administration every 4 weeks ADR: - serious infection - headache, HT, ↑liver enzyme - neutropenia, reduced platelet count - GI perforation (↑risk in diverticulitis or corticosteroid px) |
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Costimulation modulators
- give example: what it is, action, administration - ADR [2] |
Abatacept
- endogenous ligand CTLA-4 - binds to CD80 + CD86 of Ag-presenting cell, inhibiting T-cell binding and prevent T-cell activation - IV infusion over 30 min once every 2 weeks x3, followed by monthly infusion (t1/2 13 days) ADR: - infusion, HS reactions - ↑risk for infection (esp w. T inhibitors and anakinra) so combination not recommended |
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B-cell cytotoxic agent
- give example: what it is, action, administration - clinical use - ADR [2] |
Rituximab
- chimeric monoclonal Ab: targets CD20 B-cell Ag - deplete B-cell, ↓Ag presentation to T-cell, inhibit secretion of proinflamm cytokines - IV infusion (sep by 2 weeks, repeated 6-9 months) - reserved for sub-optimal response w. TNF inhibitor. given with MTX ADR: - infusion reactions (↓by IV glucocorticoids 30 mins before infusion) - ↑risk of infection |
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Adverse effects of DMARD [5]
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- ↑susceptibility to infection
- bone marrow suppression/hematologic toxicity [leukopenia, anemia, thrombocytopenia, neutropenia] - GI disturbance - HS reactions - injection site irritation |
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What is gout?
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metabolic disease where ↑plasma conc of urate.
Urate crystal deposits in synovial tissue of joints |
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Tx of gout
Name of class [4]? give example |
1. ↓formation of uric acid
- Xanthine oxidase inhibitors: allopurinol, febuxostat 2. ↑excretion of uric acid - Uricosuric agents: probenecid, sulfinpyrazone 3. Uric acid conversion to soluble allantoin - pegloticase: recombinant mammalian uricase *IV admin every 2 weeks 4. ↓inflammation during gouty attack - Colchicine: specific action of ↓inflamm during phagocytosis of urate - NSAID except salicylates! |
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MoA of xanthine oxidase inhibitor [2]
- ADR |
*allopurinol metabolised to alloxanthine,
*↓uric acid (↑hypoxanthine & xanthine) ADR: renal stones from xanthine accumulation (↑urine volume, ↑urine pH >6) |
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MoA of drugs converting uric acid to soluble to allantoin [2]
- ADR |
*↓reabsorption in proximal tubules, ↓plasma uric acid
*inhibit tubular secretion of several drugs (MTX, penicillin, active metabolite of clofibrate) ADR: renal stone from urate accumulation |
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Action of colchicine, [4]
ADR of colchicine [4] - toxicity associations |
*inhibit tubulin polymerization into microtubule
*inhibit leukocyte migration and phagocytosis *inhibit formation of leukotriene B4 *for prophylaxis at lower dose - diarrhea - nausea, vomiting, abd pain - hepatic necrosis, Acute renal failure, DIC, seizure, - hair loss and bone marrow depression (toxicity) *life-threatening toxicity ax with concomitant tx with P-glycoprotein or CYP3A4 inhibitors |
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Why aren't salicylates used to treat gout?
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↓urate excretion in low dose!
(dose-dependent: ↑uric acid excretion in large dose >5g per day, ↓uric acid excretion in 1-2 g per day) so inhibits actions of uricosurics |
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Therapeutic strategies against athritis [4]
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1. ↓pain (analgesia) w. paracetamol, NSAIDS
2. ↓inflammation w. NSAID, glucocorticoids 3. ↓progression of joint problem w. DMARD, glucocorticoids 4. ↓source of inflammation by ↓gouty attack |
