P2

• Disease-Modifying Antirheumatic Drugs (DMARDs) are used in the management of rheumatic diseases, most commonly, rheumatoid arthritis
• DMARDs are used to reduce pain and inflammation, reduce and prevent joint damage, and preserve the structure and function of the involved joints
• Goals of DMARD treatment (SCAPI)

  • Slow progression of joint damage
  • Control disease activity
  • Alleviate pain
  • Preservation of function
  • Improvement of quality of life
• Classification of DMARDs


  • Small molecules (csDMARDs)
  • Biologicals (bDMARDs)
• Small molecules (csDMARDs)


  Conventional synthetic, include small molecule drugs
• Biologicals (bDMARDs)


  Newer large molecule agents, usually proteins, which are produced by recombinant DNA technology
• Methotrexate


  An anti-folate, regarded as the DMARD of choice used in 50-70% of patients
• Mechanism of action of Methotrexate

  1. Inhibition of AICAR transformylase and thymidylate synthetase

  2. AICAR inhibits AMP deaminase, leading to an accumulation of AMP

  3. AMP is then converted and released extracellularly by adenosine, which is a potent inhibitor of inflammation

  4. Inflammatory cells (e.g. neutrophils, macrophages, and lymphocytes) are suppressed
• Pharmacokinetics of Methotrexate


  • Can be administered either orally or parenterally (subcutaneous or intramuscular)
  • Bioavailability: 64-90%
  • Distribution: 42-57%
  • Metabolism: less hydroxylated product in the liver
  • Excretion: Excreted intact via the renal route by about 70-90%
  • Half-life: 6-9 hours
  • Hydroxychloroquine can reduce the clearance or increase intertubular reabsorption of Methotrexate (MTX)
• Indications for Methotrexate


  • Rheumatoid arthritis (RA): 15-25 mg weekly
  • Juvenile chronic arthritis
  • Psoriasis
  • Polymyositis
  • SLE
  • Vasculitis
• Adverse effects of Methotrexate

  • Nausea and mucosal ulcers
  • Leukopenia, anemia, stomatitis, GI ulcerations and alopecia
  • GI and Liver Function test abnormalities
• Chloroquine & Hydroxychloroquine


  Belong to a class of drug known as 4-aminoquinolines, mainly used for Malaria, has been shown to be effective in Rheumatoid Arthritis and other Rheumatic diseases
• Mechanism of action of Chloroquine & Hydroxychloroquine

  1. T-lymphocyte response suppression

  2. Decrease in leukocyte chemotaxis

  3. Stabilization of lysosomal enzymes

  4. Inhibition of DNA and RNA synthesis

  5. Trapping of free radicals
• Pharmacokinetics of Chloroquine & Hydroxychloroquine

  • Absorption: Rapid absorbed through oral administration
  • Bioavailability: 0.7-0.8
  • Metabolism: Liver
  • Half-life: 45 days
  • Excretion: Kidneys (21% for hydroxychloroquine, 51% for chloroquine)
• Indications for Chloroquine & Hydroxychloroquine

  • Rheumatic Arthritis (But not very effective)
  • Systemic Lupus Erythematosus
  • Sjogren's syndrome
• Adverse effects of Chloroquine & Hydroxychloroquine

  • Ocular toxicity
  • GI upset
  • Rashes
  • Nightmare
• Azathioprine


  Purine synthase inhibitor, acts to its major metabolite 6-thioguanine
• Mechanism of action of Azathioprine

  Suppresses inosinic acid synthesis, T and B cell functions, Immunoglobulin (Ig) production, and IL-2 secretion
• Indications for Azathioprine


  • Rheumatoid arthritis
  • Kidney transplantation rejection
  • Systemic Lupus Erythematosus (SLE)
• Adverse effects of Azathioprine

  • Bone marrow suppression
  • GI disturbances
  • Risk for infection
  • Lymphoma

  
• Cyclophosphamide


  An alkylating agent, active metabolite is phosphoramide mustard which cross-links DNA to prevent cell replication
• Mechanism of action of Cyclophosphamide

  1. Phosphoramide mustard cross links DNA to prevent cell replication

  2. Suppresses T and B cell functions by 30% to 40%
• Indications for Cyclophosphamide


  • Rheumatoid arthritis
  • Systemic Lupus Erythematosus (SLE)
  • Vasculitis
• Cyclosporine


  Calcineurin inhibitor which is also considered a peptide antibiotic
• Mechanism of action of Cyclosporine

  1. Through regulation of gene transcription, it inhibits IL-1 and IL-2 receptor production

  2. It inhibits macrophage - T cell interaction and responsiveness
• Indications for Cyclosporine


  • Rheumatoid Arthritis
  • Systemic Lupus Erythematosus (SLE)
  • Juvenile Chronic Arthritis
• Pharmacokinetics of Cyclosporine


  • Absorption: Absorption is incomplete and erratic, although a microemulsion formulation improves its consistency and provides 20–30% bioavailability
  • Metabolism: Major site of metabolism is liver by CYP3A subjecting it into a large number of drug interaction
  • Excretion: Mainly through the feces: 70%, In the urine: 15%
• Adverse effects of Cyclosporine

  • Decrease in WBC: Leukopenia
  • Decrease in Platelets: Thrombocytopenia
  • Decrease in Hemoglobin: Anemia (into a lesser extent)
  • High doses can be cardiotoxic and neurotoxic
  • Sterility may occur after chronic dosing especially in women
• Leflunomide


  Pyrimidine synthase inhibitor that undergoes rapid conversion, both in the intestine and in the plasma to its active metabolite, A77-1726
• Mechanism of action of LeflunomideLFABIDRACIABA

  1. A77-1726 inhibits Dihydroorotate Dehydrogenase (DHODH), the rate limiting step in the de novo synthesis of pyrimidines

  2. This leads to a decrease in ribonucleotide synthesis, arrest of stimulated cells in the G1 phase of cell growth

  3. Resulting in inhibition of T-cell proliferation and reduction of production of autoantibodies by B cells
• Pharmacokinetics of Leflunomide


  • Absorption: Completely absorbed from the Gut
  • Half-life: 19 days
  • Cholestyramine can enhance leflunomide excretion and increases total clearance by approximately 50%
• Indications for Leflunomide


  • As effective as methotrexate in the management of rheumatoid arthritis, including inhibition of bony changes
  • Combined treatment with methotrexate and leflunomide resulted in a 46.2% ACR20 response compared with 19.5% in patients receiving methotrexate alone
• Dosing of Leflunomide


  • Loading dose: 100 mg OD for 3 days
  • Maintenance: 10-20 mg OD
• Adverse effects of Leflunomide

  • Diarrhea
  • Elevation in liver enzymes
  • Mild alopecia
  • Weight gain
  • Increased blood pressure
• Sulfasalazine


  Salicylate, metabolite: Sulfapyridine and 5-aminosalicylic acid, Sulfapyridine is the active moiety when treating rheumatoid arthritis
• Mechanism of action of SulfasalazineSINTAC

  Sulfapyridine acts by inhibiting the release of inflammatory cytokines (e.g. IL-1, 6, 12, and TNF-a), produced by monocytes and macrophages
• Pharmacokinetics of Sulfasalazine


  • Only 10-20% is absorbed orally, a fraction undergoes enterohepatic recirculation into the bowel where it is reduced by intestinal bacterias to liberate sulfapyridine and 5-aminosalicylic acid
  • Sulfapyridine: well absorbed
  • 5-aminosalicylic acid: remains unabsorbed
  • Half life: 6-17 hours
  • Excretion: Renal
• Indications for Sulfasalazine

  • Rheumatoid arthritis
  • Inflammatory Bowel Disease
  • Juvenile chronic arthritis
  • Dose: 2-3g/day
• Adverse effects of Sulfasalazine

  • Nausea/Vomiting
  • Rash
  • Headache
• Methotrexate is the DMARD of choice