Dmards (Moa, Pk, Dosing, Ae, Ddi)

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Non-biologic DMARDs

Back 1

Methotrexate (MTX)
Sulfasalazine
leflunomide, (LEF)
hydroxychloroquine

Front 2

MTX MOA:

Back 2

MOA: unknown in RA; possibly increased adenosine concentrations

Front 3

MTX PK:

Back 3

A: Oral:< 30 mg/m2- 90%; higher doses-decreased , IM: 76 – 100%
M: Liver
E: Renal (80-90% unchanged)
t 1/2 = 3-10 hrs (low dose); 8-15 (high dose)

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MTX Dosing:

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Initial: 7.5mg PO weekly or 2.5mg q12h x3 dose weekly.; titrate 2.5mg/weekly (Max: 30mg/week)

​Give with folic acid 1mg PO daily

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MTX AE:

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• GI: Nausea, upset stomach, loose stools
• Stromatitis
• Rash-macular
• Hematologic - myelosuppression
• Hepatoxicity (adjust for Hepatic dosing)

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MTX DDI:

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• NSAIDS-decrease MTX clearance
• PCNs, Probenecid-inhibit MTX tubular secretion
• Sulfonamides-addiitive DHFR inhibition(additive toxicity)
• AZA, sulfasalazine-addititve hepatoxicity effects
• Cyclosporine-inhibit MTX metabolism

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Sulfasalazine (Azulfidine) MOA:

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MOA: Unknown in RA; may be due to increased production of adenosine or inhibition cytokine secretion

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Sulfasalazine (Azulfidine) PK:

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A: PO – sulfasalazine (15%); sulfapyridine (60%)

M: Intestinal; Liver (sulfasalazine 15%; sulfapyridine 60%)

E: Renal (sulfasalazine and sulfapyridine);

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Sulfasalazine (Azulfidine) Dosing:

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Slow increase titration to avoid side effects.
Hepatic: AVOID USE

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Sulfasalazine (Azulfidine) AEs:

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Dose-related

• GI – anorexia, N/V/D, Stomach upset (VERY COMMON)
• Hepatic – increased AST/ALT
• Hematologic – leukopenia, hemolytic anemia, megaloblastic anemia
• Folate deficiency possible

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Sulfasalazine (Azulfidine) DDI:

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• Methotrexate – Additive hepatotoxic effects
• Cyclosporine – Induce cyclosporine metabolism
• Digoxin – Decrease digoxin absorption

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Leflunomide (Arava) MOA:

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MOA: Inhibits B & T-cell activation
(Inhibits dihydroorotate dehydrogenase blocking synthesis of ribonucleotide uridine monophosphate pyrimidine)

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Leflunomide (Arava)PK:

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A: ORAL 80%
D: 99% PB;
M: GI and Liver (Prodrug; active metabolite teriflunomide); extensive enterohepatic recirculation
E: Renal (43%); Feces (48%)
t 1/2 = 11 days (metabolite)

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Leflunomide (Arava) Dosing:

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20 mg PO daily,Loading dose of 100 mg PO daily x 3 days can be considered (sometimes avoided), but less side effects
Renal: Lacking data; Use caution
Hepatic: Not recommended for use

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Leflunomide (Arava) AE:

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• GI: Nausea and Diarrhea
• Hepatic – Increased AST/ALT - 13 %
• Hematologic – Leukopenia, thrombocytopenia, pancytopenia
• Peripheral neuropathy

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Leflunomide (Arava) DDI:

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Methotrexate – Additive hepatotoxic effects
Rifampin – Induces leflunomide metabolism increasing teriflunomide levels
Warfarin - Inhibits warfarin metabolism

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Hydroxychloroquine (Plaquenil) MOA:

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Antimalarial drug - Unknown

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Hydroxychloroquine (Plaquenil) PK:

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A: ORAL 74%
M: Liver
E: Renal (16-25%)
t 1/2 = 40 days (up to 6 wks for full effect)

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Hydroxychloroquine (Plaquenil) Dosing:

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200 mg – 300 mg PO BID; Maintenance: 200 mg - 400 mg PO Daily

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Hydroxychloroquine (Plaquenil) AE:

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• GI – N/V/D (take with food)
• Alopecia
• Skin pigmentation
• Ocular – impaired accommodation, corneal deposits, blurry vision, scotomas, night blindness

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Hydroxychloroquine
(Plaquenil) Monitoring:

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Ophthalmologic exam (baseline and every 3 months)

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Biologic DMARDs

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genetically engineered recombinant protein molecules or monoclonal antibodies.

Used when other DMARDs fail

• TNF-α Blockers (5)
• Interleukin Receptor Blockers (2)
• T-cell activation inhibitor
• B-cell cytotoxic agent

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TNF-α Blockers (1st line biologic DMARDs)

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• Etanercept (Enbrel®)
• Infliximab (Remicade®)
• Adalimumab (Humira®)
• Golimumab (Simponi®)
• Certolizumab (Cimzia®)

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Anakinra (Kineret®) MOA:

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-IL-1 Receptor Antagonist

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Tocilizumab (Actemra®) MOA:

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-IL-6 Receptor Antagonist

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Abatacept (Orencia®) MOA:

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- Inhibition T-cell activation (Binds to CD80/CD86 receptor on APCs)

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Rituximab (Rituxan®) MOA:

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-B-cell cytotoxic agent (Binds to CD20 on B cells )

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Etanercept ROA & AE:

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SC

• Injection reactions
• Infection
• Tuberculosis
• Malignancy
• Neutropenia
• Thrombocytopenia
• Multiple Sclerosis
• Heart Failure

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Infliximab ROA & AE:

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IV infusion (give with MTX)

(Pretreatment for infusion reactions Acetaminophen/diphenhydramine/corticosteroids)

• Infusion reactions
• Infection
• Tuberculosis
• Malignancy
• Neutropenia
• Thrombocytopenia
• Multiple Sclrosis
• Heart Failure

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Adalimumab ROA & AE:

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SC

• Injection reactions
• Infection
• Tuberculosis
• Malignancy
• Neutropenia
• Thrombocytopenia
• Multiple Sclerosis
• Heart Failure

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Golimumab ROA & AE:

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SC (give with MTX)

• Injection reactions
• Infection
• Tuberculosis
• Malignancy
• Neutropenia
• Thrombocytopenia
• Multiple Sclerosis
• Heart Failure

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Certolizumab ROA & AE:

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SC

• Injection reactions
• Infection
• Tuberculosis
• Malignancy
• Neutropenia
• Thrombocytopenia
• Multiple Sclerosis
• Heart Failure

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Anakinra ROA & AE:

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SC

• Injection reactions
• Infection
• Malignancy
• Neutropenia
• Thrombocytopenia

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Tocilizumab ROA & AE:

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IV Infusion

• Infusion reactions
• Infection
• Tuberculosis
• Malignancy
• Neutropenia
• Thrombocytopenia
• Hyperlipidemia
• Increased AST/ALT
  
  

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Abatacept ROA & AE:

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SC

IV Infusion

• Injection reactions
• Infusion reactions
• Infection
• Tuberculosis
• Malignancy

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Rituximab ROA & AE:

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IV Infusion

(Pretreatment for infusion reactions:
Methylprednisolone 100 mg IV
Acetaminophen/diphenhydramine)

• Infusion reactions
• Infection
• Malignancy
• Neutropenia
• Thrombocytopenia
• Increased AST/ALT

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DMARDs MOA

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