Ra And Gout

Front 1

Hydroxychloroquine overview

Back 1

Used for mild RA
Administered daily (weekly when anti-malarial)
Unknown mechanism

Front 2

Hydroxychloroquine observed effects

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Takes 12-24 weeks before effect
Rapidly and completely absorbed
Half-life of 40-50 days

Front 3

Hydroxychloroquine toxicity

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Accumulates in lung, kidney, spleen, heart, and MELANIN-CONTAINING STRUCTURES - esp. retinal pigment epithelium
Can cause irreversible blindness

Front 4

Hydroxychloroquine contraindications

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Eye, neurological, or hepatic disease
Kids especially sensitive

Front 5

Doxycycline

Back 5

For mild RA
Inhibits activity of metalloproteases involved in joint destruction
Used as adjunctive therapy early in disease

Front 6

Sulfasalazine

Back 6

For mild RA
Decreases IgA and IgM rheumatoid factor
Reduces rate of appearance of new joint damage
30% discontinue due to toxicity

Front 7

Methotrexate overview

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For mild RA with definitive diagnosis
First DMARD of choice

Front 8

Methotrexate mechanism in RA

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At concetration used, inhibits AICAR transformylase
Functions as immunosuppressant
Decreases rate of new lesion formation

Front 9

Methotrexate toxicity

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MC - nausea, mucosal ulcers
Hepatotoxicity (enzyme elevation) common, cirrhosis rare
Monitor for liver and lung toxicity
35% discontinue due to toxicity

Front 10

Methotrexate contraindications

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Pregnancy and liver disease
Males should be cautious if wife trying to get pregnant - 3 months before conception

Front 11

Leflunomide mechanism

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For mild RA with definitive diagnosis
Inhibits pyrimidine synthesis - inhibits dihydroorotate dehydrogenase - synthesis of UMP

Front 12

Leflunomide vs. MTX

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Similar efficacy, but withdrawal for adverse effects more common
Used in patients who can't tolerate MTX, or if monotherapy not effective

Front 13

Leflunomide adverse effects

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Diarrhea and nausea
Hepatotoxicity
HTN (rare)
Monitor liver enzymes
Long half life due to enterohepatic recycling

Front 14

Treatment of aggressive RA

Back 14

Use TNF-alpha blocking agents
Often used in conjunction with MTX

Front 15

Etanercept

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Enbrel
Recombinant fusion protein - extracellular portion of TNF-alpha receptor linked to Fc portion of IgG
SQ twice per week
Monotherapy or with MTX
Improves symptoms, prevents new lesions
Adverse - latent TB, opportunistic infection, lymphoma, expensive

Front 16

Adalimumab

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Humira
Recombinant human anti-TNF-alpha monoclonal Ab
Same mechanism as inflixamab, administered SQ
Monotherapy or with others
Adverse effects like etanercept

Front 17

RA combination therapy

Back 17

Anti-TNF alpha + MTX
~50% go into remission
Significant improvement in another 20%
Prevents additional joint damage; MTX+Enbrel can repair
$12K-50K/year

Front 18

Anakinra

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For RA
Naturally occurring IL-1 receptor antagonist
Not great for RA
DOC for treatment of periodic febrile illnesses (Muckle Wells)

Front 19

Abatacept

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Approved for RA refractory to TNF-alpha inhibition
Selectivity modulates costimulatory signal required for full T cell activation

Front 20

Purine metabolism and gout

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High de novo activity increases purine turnover - higher plasma urate
- PRPP level is most important determinant
Increased activation of salvage pathway depletes PRPP, thus decreasing de novo synthesis
Degradation by single, convergent pathway
Uric acid highly insoluble

Front 21

Gout pathophysiology

Back 21

Increased plasma uric acid correlates with likelihood of gout
Lower temps promote crystal formation (toe)

Front 22

NSAIDs in gout

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Ibuprofen and indomethacin, celecoxib potentially
If contraindications, use GCs
If unresponsive, prednisone

Front 23

Colchicine mechanism

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Used in acute gout
Inhibits polymerization of tubulin - inhibits cell divison, intracellular trafficking, PMN activation
Undergoes extensive enterohepatic recycling, excretion into bile regulated by hepatic multidrug-resistance (MDR) protein

Front 24

Colchicine uses

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Treat and prevent gout recurrence
95% benefit, not effective in other forms of arthritis
Lower doses for maintenance

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Colchicine adverse effects

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GI - diarrhea common
Myelosuppression, esp high doses

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Colchicine drug interactions

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Cyclosporine and tacrolimus inhibit MDR protein and are nephrotoxic - compromise excretion
Verapamil also inhibits MDR

Front 27

Allopurinol mechanism

Back 27

For chronic gout
Low levels - competes with xanthine and hypoxanthine for xanthine oxidase
At high levels, oxidized to oxypurinol, noncompetitive inhibitor of xanthine oxidase
Decreases uric acid, increases xanthine/hypoxanthine (moderately soluble)

Front 28

Allopurinol uses

Back 28

Chronic gout, esp with excess urate production
Not for acute gout - disruption of urate homeostasis can worsen attack
NSAID or colchicine administered during initial therapy - prevent acute gout attack
Used in chemotherapy/radiotherapy, patients with leukemia, Lesch-Nyhan

Front 29

Allopurinol adverse effects

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Well tolerated
Hypersensitivity reactions - rash - must discontinue due to potential for Stevens-Johnson syndrome

Front 30

Allopurinol drug interactions

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Theophylline, azathioprine, 6-MP - metabolized via xanthine oxidase pathway - decrease doses

Front 31

Febuxostat mechanism

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For chronic gout
Xanthine oxidase inhibitor

Front 32

Febuxostat Uses

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Chronic gout
More efficacious than allopurinol at lowering urate levels
No dose reduction required in geriatric patients, or patients with mild-moderate renal impairment

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Febuxostat adverse effects

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MC - liver function abnormalities
Prophylaxis with NSAID/colchicine required for therapy initiation

Front 34

Febuxostat drug interactions

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Theophylline, azathioprine, 6-MP

Front 35

Probenecid mechanism

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Uricosuric agent (organic acid)
Inhibits basolateral anion exchanger in proximal tubule - blocks urate reabsorption

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Probenecid uses

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Treatment of chronic hyperuricemia

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Probenecid adverse effects

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Predisposes to formation of urate stones in kidney or ureter
- Prevent by alkalinization of urine by coadmin of oral calcium citrate or sodium bicarb
Renal stones are contraindications
Allergy (rash), GI distress, aplastic anemia (rare)

Front 38

Probenecid drug interactions

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Increases plasma levels of many organic anions and drugs, esp. penicillin
Orignially developed to increase penicillin levels
Low dose aspirin antagonizes - more uric acid reabsorption
High dose aspirin does opposite - uric acid reabsorption decreased