Medchem DMARDs/GOUT

What are signs of rheumatic diseases

inflammation, tissue alteration, connective tissue damage

What can happen if underdose uricosuric drugs

sub therapeutic can inhibit uric acid secretion, need therapeutic dose to inhibit reabsorption

Why is it important to treat rheumatic diseases early

progressive, cause irreversible damage

How are rheumatic disease generally treated

dampening inflammation, immunosuppression

What are some risk factors for rheumatic disorders

• more common in women

• Some are genetic (rheumatoid arthritis)

• Environmental factors (triggers disease)

Rheumatoid arthritis pathogenesis

immune response to rheumatoid factor causing attack on healthy tissue

• causes extra growth in joints (pannus) , causing rubbing against each other

Symptoms of rheumatoid arhritis

synovial inflammation is main but many other symptoms

Rheumatoid arthritis risk factors

Women 3x more likely

genetic disposition + antigenic trigger

Older, around 50

What is Lupus

chronic inflammatory disease in whole body with production of ANA

What are ANA

antibodies for components of nucleus of cells

How are B and T cells effects in Lupus

abnormal B and T cell function, B cells cannot properly eliminate self-reactive cells

Butterfly rash

indicative of lupus

What is scleroderma

thickening and hardening of skin and joints and organs

Localized versus systemic scleroderma

local - usually only skin

systemic - includes internal tissues

What is osteoarthritis

wear and tear arthritis → secondary inflammation

degenerative joint disease

What are DMARDs

disease modifying anti-rhematic drugs

• work to suppress overactive immune and inflammation symptoms

• take over long-term for effects

  • usually combined with NSAIDs and glucocorticoids

Methotrexate onset

3-6 weeks, faster than others

Methotrexate use

Rheumatoid Arthritis, lower dose than anti-cancer

Methotrexate MOA

Inhibits Dihydrofolate reductase

• no folate to THF (folate supps)

reduces production of inflammatory cytokines

inhibits DNA/RNA synthesis and B cell proliferation

downregulates immune system

increase Adenosine

Methotrexate Adverse

CNS dizziness, memory, mood

Mouth soures

N/V

Alopecia

Take Folate supps

Methotrexate elimination

Kidney’s, avoid if renal failure

Leflunomide active form

prodrug to teriflunomide

Leflunomide uses

Rheumatoid arthritis, Lupus, Psoriasis

Leflunomide MOA

Inhibits de novo pyrimidines by inhibiting dihydroorotate dehydrogenase, lowering DNA synthesis and lowering B cell proliferation, lowering inflammatory cytokines and immune system

Leflunomide Adverse

BBW - hepatotoxicity

pancytopenia

teratogenic

Sulfasalazine breaks into

Sulfapyridine antibiotic and 5-aminosalicylic acid

Sulfasalzaine uses

Crohn’s, ulcerative colitis, with methotrexate for rheumaotoid arhritis

Sulfasalazine MOA

Inhibits prostaglandin synthesis

Inhibits purine biosynthesis

Sulfasalazine Adverse

mild: skin sensitivity, GI upset

severe: bone marrow suppression, hepatitis

Azathioprine active form

prodrug to 6-mercaptopurine

Azathioprine MOA

Inhibits purine synthesis → less B and T cells, less IgGs, less Il-2

Azathioprine uses

Rheumatoid arthritis, lupus, transplant rejection

Azathioprine Adverse

Neutropenia, thrombocytopenia, teratogenic

Azathioprine metabolism

TPMT is needed to eliminate toxic metabolites, some individuals are deficient

Tofacitinib MOA

JAK inhibitor (3 and 1)

Tofacitinib adverse

neutropenia, anemia, infections (similar to biologics even though not true biologic

What are TNF-a inhibitors used for

crohn’s, ulcerative colitis, rheumatoid arthritis,

TNF-a inhibitor MOA

lowers Il-6 and Il-1

reduce MMPs

lymphocyte activation

TNF-a inhibitor Adverse

neutropenia, increase risk of infection and cancer

Adalimumab MOA

Anti-TNF-a antibody

Enanercept

Soluble TNF-a receptor

Rituximab MOA

anti CD20 Ab, lowers B lymphocytes by NK killing of B cells

What is rituximab used with

Methotrexate

Abatacept MOA

CTLA4 soluble receptor - intercepts antigens from activating T cells via CTLA4:CD80

• immunosuppressive

Abatacept uses

Rheumatoid disorders

Abatacept adverse

increased risk of infection, worsens COPD

Tocilizumab MOA

Ab for Il-6 receptor , sequestering inflammatory cytokine receptor → no binding

restore normal CYP functioning

Tocilizumab uses

All kinds of arthritis

Anakinra MOA

Competitive inhibitor of Il-1 receptor

Canakinumab MOA

Neutralizes IL-1B

Canakinumab Use

Juvenile Idiopathic Arthritis

What biologics should not be combined

TNF-a inhibitors and IL-1 antagonists should not be used together

What are some contraindications of IL-1 inhibitors

neutropenia, Latent TB, Asthma, live vaccines

What causes Gout

crystallization of uric acid in joint

How does acidification affect gout

one crystal → more acid → more crystals

What can cause hyperuricemia

high protein intake, alcoholism, diuretics, thiazide diuretics which lower excretion of uric acid, low dose aspirin

Colchicine MOA

disrupts microtubules, inhibits lactic acid production, preventing inflammatory cell migration, increases pH of connective tissues, increase uric acid solubility

Colchicine use

rapid relief of gout,

Colchicine adverse

GI distress, Renal toxicity

What are 2 uricosuric drugs

probenecid, sulfinpyrazone

How do uricosuric drugs work

prevent reabsorption of uric acid by blocking URAT1

Uricosuric drug use

not for acute gout, no inflammation, chronic gout use

Probenecid Contraindications

renal failure, extreme hyperuricemia

What are 2 xanthine oxidase inhibitors

allopurinol, febuxostat

Xanthine oxidase inhibitor use

long-term treatment of gout, preferred is uricosuric not good choice

Xanthine oxidase inhibitors adverse

SJS

hypersensitivity

decrease metabolism of azathioprine and 6-mercaptopurine

What are gold salts

Drugs with Au+S for arthritis

Hydroxychloroquine use

Antimalaria

Apremilast MOA

Inhibits PDE4

Apremilast Use

Psoriasis

What are the 3 approaches to treatment for gout

Decrease inflammation from deposition

• Colchicine, indomethacin

Decrease tubular reabsorption

• probenecid, sulfinpyrazone

Decrease uric acid production

• allopurinol

How does allopurinol inhibit xanthine oxidase

reversible competitive inhibition 15-20x better

What does xanthine oxidase due to allopruinol

metabolizes allopurinol to alloxanthine which is a non-competitive inhibitor of xanthine oxidase

Allopurinol DDIs

inhibits some liver enzymes that are needed for eliminating anticoagulants