Drugs for Arthritic Disease

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Dr. Turnbull - October 13, 2011 Semester 3, Mini 2

What are the drugs acting against circulating proinflammatory cytokines?

Infliximab, Adalimumab,
Etanercept, and Anakinra

What is infliximab and how does it work?

human/mouse chimeric monoclonal IgG1 Ab, w/ human Fc and murine variable regions that bind soluble and transmembrane TNF-α

What are the uses of infliximab?

RA, Ankylosing spondylitis, Psoratic arthritis, Crohn's Dis, Ulcerative colitis, IBD

What is usually used in combination w/ infliximab?

methotrexate

Why might a serious infection, like TB, occur as a result of infliximab administration?

↓ macrophage function

What are some common side effects of infliximab?

headache, fatique, abdominal pain, infusion reaction, upper respiratory/UTIs

What is a possible adverse effect when taking infliximab in combination w/ azathioprine?

T-cell lymphoma

What is the difference b/w infliximab and adalimumab structure?

Adalimumab is fully humanized monoclonal IgG1 ab
(no murine component)

What are the uses of adalimumab?

Ankylosing spondylitis
Crohn's disease
Psoriasis with arthropathy

How does adalimumab work?

Fully human ab that blocks the interaction of TNF-α with TNF receptors on cell surfaces.
Also: ↓ C reactive protein, ↓ ESR, ↓ IL-6, ↓ MMP-1 & MMP-3.

How might you have to adjust the dose of adalimumab after adding methotrexate to the drug regiment?

↓ adalimumab
(methotrexate ↑ t½)

What is the black box warning for adalimumab?

At risk for TB, invasive fungal infections, and other opportunistic infections.
Adverse effects: exacerbates chronic CHF, serious infections, lupus-like syndrome.

How is adalimumab administered?

SQ every 14 days

What is the structure of Etanercept?

soluble, recombinant fully human TNF receptor fusion protein receptor
(extracellular domain of the TNF-α receptor coupled to human IgG1)

How does etanercept work?

It inhibits the binding of TNF-α and TNF-β to their
receptors, thus ↓ inflammation due to TNF-α.

What is etanercept used for?

moderate to severe RA
psoriatic arthritis
juvenile arthritis

What drug against proinflammatory cytokines is C/I in pts w/ MS?

etanercept

What is the structure of Anakinra?

recombinant form of Human IL-1 receptor antagonist

What is the main use of anakinra?

RA

What is a serious adverse effect of anakinra?

infection, ↓ WBCs

What are the miscellaneous DMARDs?

D-penicillamine
Chloroquine/Hydroxychloroquine
Sulfonamide plus salicylate (sulfasalazine)

What patients are given miscellaneous DMARDs?

NSAID non-responders
non-compliant patients
patients w/ serious GIT problems w/ NSAIDS and steroids
patients whose joints are deteriorating rapidly
Juvenile RA

What are some ways you evaluate the efficacy of a miscellaneous DMARD?

pain score
articular index (size of joint)
measure rf
measure acute phase proteins
test joint movement

What is the MoA of penicillamine?

unknown

Penicillamine is rarely used in the tx of RA now, what is its main use?

Wilson's disease

How is penicillamine administered?

oral

What are some major adverse effects of penicillamine?

*Blood dyscrasias-bone marrow suppression which may be fatal*
hypersensitivity reactions
Autoimmune disorders

If a patient on penicillamine develops proteinuria, what is the best next step?

alternate therapy
(unwise to substitute this DMARD w/ another)

What are the second line drugs used in the tx of RA?

Hydroxychloroquine/chloroquine

What is chloroquines used for other than RA?

anti-malaria
SLE

How does chloroquines work?

Suppresses the responsiveness of T- lymphocytes to mitogens
Decreases leukocyte chemotaxis
Stabilizes lysosomal membranes
Inhibits DNA and RNA synthesis
Reduce oxidative reactions

What is a major possible adverse effect of chloroquines?

irreversible retinal degeneration
(dose and frequency related)

Besides RA, what is another use of sulfasalazine?

ulcerative colitis

Where is sulfasalazine metabolized to its active metabolite?

In the gut by bacteria.

What type of people would show increased effects with sulfasalazines?

slow-acetylators

How does sulfasalazines reduce inflammation?

cox inhibitor in the gut

What adverse effects of sulfasalazines occur in the first 3-6 months and then usually abate?

Leukopenia
thrombocytopenia

What are the most common side effects of sulfasalazine?

nausea and vomiting
diarrhea and anorexia

What are the major cytotoxic drugs?

methotrexate, azathioprine,
leflunomide, cyclosporine

What is the most commonly prescribed DMARD?

methotrexate

How does methotrexate work?

inhibits DHFR

What is the difference in RA and cancer tx with methotrexate?

low dose in RA

What is given as an adjunct therapy in conjunction with methotrexate?

folate

What are some of the most common toxicities associated with long-term methotrexate therapy?

Nausea, vomiting, diarrhea, anorexia
Leucopenia
MTX lung
Hepatotoxicity

What tests are mandatory when a pt is on methotrexate?

CBC's and LFT's
(checking level of hepatoxicity)

How does azathioprine work?

inhibits PPRP synthase
(purine synthesis)

How does leflunomide work?

inhibits dihydro-orotate DH
(RTL of de novo pyrimidine synthesis)

What are the uses of leflunomide

moderate to severe RA
psoriatic arthritis

Why does leftunomide decrease B and T cell proliferation?

B and T cells depend on de novo pyrimidine synthesis (can't recycle?). Leftunomide blocks this.

What are some adverse effects of leflunomide?

GI tox
↑ transaminases
Rash and allergic reactions
Reversible alopecia
Headache
Renal impairment

What drug is second line following methotrexate?

leflunomide

What are both methotrexate and leflunomide C/I in?

pregnancy!

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