5 DMARDs Flashcards by Hannah Frank

What are the goals of therapy for chronic inflammatory diseases?

Relief of pain
Reduction of inflammation
Protection of articulate structures
Maintenance of function
Control of systemic involvement

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What are the different drug classes that can be used for the treatment of chronic inflammatory disease?

NSAIDs (cox-inhibitors)

Disease Modifying Anti-Rheumatic Drugs (DMARDs)
• Not analgesic and take time to work
• Various MOAs

Cortical steroids
• Inhibit AA release
•Inhibit immune response

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How do Gold Salts work?

SUPPRESS CELLULAR IMMUNITY

Inhibition of phagocytosis
Uncouple oxidative phosphorylation and inhibit cellular respiration
Stabilize lysosomal membranes and inhibit actions of lysosomal enzymes
React with proteins (sulfhydryl groups)
Inhibit proteolytic enzymes of leukocytes
Prevent prostaglandin synthesis

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Toxic effects of gold salts

BONE MARROW DAMAGE

Dermatitis

ENTEROCOLITIS

Jaundice

Peripheral neuropathy

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Chelating drug that is effective in both rheumatoid arthritis and Wilson’s disease

Penicillamine

Exact mechanism unknown but somewhat resembles gold compounds and may be as effective as gold

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What toxicities are possible with penicillamine

Pruritis, rash, alteration in taste

Thrombocytopenia, leukopenia, agranulocytosis, aplastic anemia

Proteinuria, hypoalbuminemia, Nephrotic Syndrome

Lupus-like disease, pemphigus, Goodpasture’s syndrom, myasthenia gravis, polymyositis, stenosis alveolitis

Patients over 65 have higher risks

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Hydroxychloroquine (Plaquenil) possesses _______, ________, and _______ properties

Antihistaminic

Anticholinesterase

Antiprotease

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MOA for hydroxychloroquine (Plaquenil)

Inhibits prostaglandin synthesis, biosynthesis of mucopolysaccharide, and responses to chemotactic stimuli and phagocytosis

Stabilizes lysosomes

Reacts with nucleic acids and tissue proteins

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Hydroxychloroquine (Plaquenil) toxicities

Pruritis

Hemolysis (G6PD deficient)****

Ototoxicity

Retinopathy

Peripheral neuropathy

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Prodrug that was originally used to treat inflammatory bowel disease but now used to RA

Sulfasalazine (Azulfidine)

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How does sulfasalazine compare to gold salts and penicillamine?

Equi-effective with injectable gold compounds and is better tolerated

As effective as penicillamine and less toxic

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Toxicities of sulfasalazine

GI disturbances, rash

Hepatitis and blood dyscrasias are rare

Monitor for hepatitis and marrow suppression is recommended for 2-3 weeks during first three months of treatment and less frequently thereafter

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Chimeric IgG1k monoclonal antibody targeted against tumor necrosis factor alpha (TNFa)

Infliximab (Remicade)

Model agent of the class

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What is the target of Infliximab (Remicade)

Chimeric IgG1k monoclonal antibody targeted against tumor necrosis factor alpha (TNFa)

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Infliximab is composed of …

Human constant and murine variable regions (it’s chimeric)

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How is Infliximab (Remicade) used?

Approved for Crohn’s disease and rheumatoid arthritis

Combined with methotrexate

Administered intravenously

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Adverse reactions to infliximab (Remicade)

HA and infusion reactions

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Contraindications for Infliximab (Remicade)

Pregnancy
Breast feeding
Children
Infections

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Recombinant human IgG1 monoclonal antibody specific for tumor necrosis factor alpha (TNFa)

Adalimumab (Humira)

Has human-derived heavy and light chain variable regions and human IgG1:k constant regions (100% human peptide)

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MOA for Adalimumab (Humira)

Recombinant human IgG1 monoclonal antibody specific for tumor necrosis factor alpha (TNFa)

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Why does Adalimumab (Humira) not have hypersensitivity reactions like other DMARDs?

It’s not chimeric - it’s composed of 100% human peptide sequences)

Which drug is formally FDA approved for monotherapy in the treatment of RA?

Adalimumab (Humira)

How is Adalimumab (Humira) administered?

SQ, half-life about 8-10 days

Most common adverse events reported by patients taking Adalimumab (Humira)

Rash
Flu-like sx
Fatigue
HA
Pruritis
N/V

NO hypersensitivity reactions

Humanized antibody that is a potent neutralizer of TNFa

Certrolizumab pergola (Cimiza)

Human-derived monoclonal antibody with human-derived variable and constant regions TNFa

Golimumab

Dimeric fusion protein produced by recombinant DNA technology and consisting of the extracellular ligand-binding portion of the human 75 kilo dalton (p75) tumor necrosis factor receptor

Etanercept (Enbrel)

MOA for Etanercept (Enbrel)

Inhibits tumor necrosis factor by blocking its receptor

Adverse effects of Etanercept (Enbrel)

Injection site reaction Infections Increased incidence of antibody formation

Contraindications for Etanercept (Enbrel)

``` Bone marrow suppression Breast-feeding Children DM Infection Sepsis Vaccination Varicella ```

Chimeric murine/human monoclonal antibody that binds specifically to CD20, a B-lymphocyte differentiation antigen on pre-B and mature B-lymphocytes

Rituximab (Rituxan)

MOA for Rituximab (Rituxan)

Chimeric murine/human monoclonal antibody that binds specifically to CD20, a B-lymphocyte differentiation antigen on pre-B and mature B-lymphocytes

Where is the target of Rituximab (CD20) found?

Expressed on >90% of B-cell non-Hodgkin’s lymphoma but not on hematopoietic stem cells, pro-B cells, normal plasma cells, or other normal tissues

How is Rituximab used?

For the treatment of relapsed or refractory B-cell NHL and is being studied in other B-cell malignancies, including chronic lymphocytic leukemia

Fully human recombinant fusion protein categorized as a costimulatory or second-signal blocker of T cell activation

Abatacept (Orencia) Competes with CD28 (on T cell) for CD80 and CD86 binding —> disturbs a key mechanisms of inflammation and progressive joint destruction in RA

Inhibitor of dihydroorotate dehydrogenase (DHODH), an enzyme located in cell mitochondria that catalyze a key step in de novo pyramiding synthesis

Leflunomide (Arava)

Secondary MOA for Leflunomide (Arava)

Inhibition of cytokines and growth factor receptor associated tyrosine kinase activity Inhibits the induction of COX-2

Contraindications for Leflunomide (Arava)

Pregnancy Breast feeding Hepatic failure Renal failure

Prodrug that inhibits lymphocyte purine synthesis by reversible and noncompetitively inhibiting the enzyme in Osi energy monophosphate dehydrogenase (IMPDH)

Mycophenolate mofetil (Cellcept)

MOA for Mycophenolate mofetil (Cellcept)

Prodrug that inhibits lymphocyte purine synthesis by reversible and noncompetitively inhibiting the enzyme in Osi energy monophosphate dehydrogenase (IMPDH)

What are the two Interleukin receptor antagonists we discussed?

Anakinra (Kineret) Tocilizumab (Actemra)

Recombinant, non-glycosylated form of the human interleukin-1 receptor antagonist (IL-1Ra)

Anakinra (Kineret)

How is Anakinra (Kineret) used?

RA patients experienced improvements of swollen and painful joints within 4-13 weeks

Contraindications for Anakinra (Kineret)

Breast feeding Children Hypersensitivity reactions Renal disease

Humanized interleukin-6 (IL-6) receptor-inhibiting monoclonal antibody

Tocilizumab (Actemra) Competes with IL-6 for binding

What drug is used to treat adults with moderate-severe RA who have an inadequate response or are intolerant to methotrexate?

Tofacitinib (Xeljanz) - a Janus kinase (JAKs) inhibitor

MOA for Tofacitinib (Xeljanz)

Primarily inhibits JAK1 and JAK3 and to a lesser extent JAK2

What is the major drawback of Tofacitinib (Xeljanz)?

Serious infections and malignancies may be precipitated by tofacitinib

Oral Janus kinase (JAK) inhibitor with a greater affinity for JAK1 and JAK2 relative to JAK3

Baricitinib (Olumiant)

Indications for Baricitinib (Olumiant)

Treatment of adult patients with moderate-severe active RA May be used as a monotherapy or in combo with methotrexate or other non-biologic DMARDs

What are the boxed warnings for Baricitinib (Olumiant)?

Risk for serious infections, malignancy, and thrombosis