Pharmacology Of Drugs For Rheumatological Disorders Iib: Dmards

Front 1

What is rheumatoid arthritis (RA)?

Back 1

• Chronic systemic inflammatory immune disease (different from osteoarthritis) → Matrix metalloproteinases (MMPs) attack the joints causing the synovium to swell
  
  
• Primary targets: Synovial tissues, bone erosion, joint deformities, Scarring of lungs, lung nodules, pleural diseases
  
  
• Affecting about 0.8% of the population → substantial premature death
  
  
• More common in women than men (3:1)
  ► Genetic predisposition: HLA-DRA-related antigen
  ► Can start at any age

Front 2

Describe about Systemic Lupus Erythematosus (SLE)

Back 2

• Chronic systemic inflammatory autoimmune disease, most commonly anti-nuclear protein antibodies
  
  
• Primary targets: Connective tissues of blood vessels & joints
  

• Affects about 2 to 7 in 10,000 of adult population
  ► More common in women than in men (9:1)
  
  
• "Great imitator" - often mimics or mistaken for other illnesses
  ► No cure and fatal → therapeutic aim is to suppres progression

Front 3

Describe non-biological DMARDs (Methotrexate)

Back 3

• Folic acid analogue
  
  
• 1st-line DMARD therapy for RA
  
  
• Often combined with other DMARDs
  
  M.O.A
• Anti-proliferative effects on T-cells and macrophage functions inhibitions, ↓ cytokines and other pro-inflammatory mediators
  ► ↑ intra- and extracellular adenosine (needed for DNA to build T-cell) due to 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) transformylase/IMP cyclohydrolase (ATIC) inhibition
  
  ► ↓ pyrimidines die to thymidylate synthase inhibition
  
  ► Dyhydrofolate reductase inhibition (minor action)
  
  Adverse effects/Precautions:
  Targeting rapidly-dividing cells, minimized by giving folate 12 - 24h after
• Nausea
• Mouth and GI ulcers
• Hair thinning
  
  
• Myelosuppression (WBC production suppression in bone marrow)
• Hepatotoxicity
• Pneumonitis (idiosyncratic)
• Pulmonary fibrosis (debatable)
  
  Contraindication
  
• Renal impairment (eliminated in urine)

Front 4

Describe non-biological DMARDs (Leflunomide)

Back 4

• "Methotrexate-lite" - similar uses and toxicity but generally less effective
  
  M.O.A
  
• Anti-proliferative effects on T-cells and inihibits B-cell auto-antibody production
  
  
• Inhibits dihydroorotate dehydrogenase (↓ pyrimidine synthesis)
  
  
• Inhibits NF-kappaB activation of proinflammatroy pathways
  
  Adverse effects
• Nausea, Vomiting and Diarrhoea
• Myelosuppression
• Hepatotoxicity
• Pulmonary fibrosis (debatable)
• Very long half life
  ► Cholestyramine wash-out (as drug has tetratogenic effects)

Front 5

Describe non-biological DMARDs (Sulfasalazine)

Back 5

• Rarely used alone but often incombination with methotrexate and hydroxycholoroquine for RA
  
  
• Metabolized to sulfpyridine (active) + 5-aminosalicyclic acid
  
  M.O.A
• Mechanism not known but poorly absorbed so may be mediated by effect on gut microflora and leads to
  ► ↓ IgA and IgM rheumatoid factors
  ► T & B cells and macrophages suppression
  ► ↓ inflammatory cytokines
  
  Adverse effects
• Nausea, Vomiting, GI upset
• Oligospermia - ↓ sperm production (reversible)
• Cytopenia/neutropenia - Often "2nd hit" rather than effect of sulfasalazine alone

Front 6

Describe non-biological DMARDs (Hydroxychloroquine)

Back 6

• Anti-malarial agent shown to benefit RA & SLE
  
  
• RA: rarely used alone but often in combination with methotrexate
  
  M.O.A
  
• ↑ pH of intracellular vesicles
  
  
• Block Toll-like receptor 9 (pathogen recognition and activation of innate immunity)
  
  
• Shields endothelial annexin V, blocks antiphospholipid antibodies (?)
  
  Adverse effects
• Nausea and vomiting
  
  
• Ocular toxicity (dose by ideal weight for height not actual weight)
  ► Bull's eye maculopathy
  ► Retinal pigment epithelial cell depigmentation
  ►Corneal "halos"
  
  
• Cardiomyopathy (rare)

Front 7

Describe non-biological DMARDs (Azathioprine)

Back 7

• Used to treat SLE, especially with nephritis
• Drugs is toxic
  
  M.O.A
• Inhibits de novo purine synthesis (mainly in lymphocytes) via thioguanine metabolites production → ↓ DNA → ↓ WBC → ↓ targeting rapidly dividing cells
  
  REFER TO NOTES FOR AZATHIOPRINE METABOLISM
  
  Adverse effects
• Nausea and Vomiting
• Myelosuppression

Front 8

Describe non-biological DMARDs (Mycophenolate)

Back 8

• SLE, especially with nephritis
• Can replace azathioprine
  
  M.O.A
• Inhibits de novo purine synthssis via inhibition of inosine monophosphate
  
  Adverse Effects
• N/V/D
• Myelosuppression

Front 9

Describe non-biological DMARDs (Cyclophosphamide)

Back 9

• SLE, especially with nephritis
• Potent by highly toxic (last resort drug)
  
  M.O.A
• DNA alkylation
  
  Adverse effects
• Haemorrhagic cystitis
• Infection
• Mylosuppression
• Bladder cancer
• Ovarian failure
• Nausea, vomiting and diarrhoea
• Alopecia (spot baldness)

Front 10

Describe biological DMARDs (TNF-alpha inhibitors)

Back 10

• For RA patients who do not respond to non-biological DMARDs
  
  
• Often used in combination with methotrexate
  
  Adverse effects
• Infections
• Increased risk of lymphoma
• Exacerbation of multiple sclerosis
• Drug-induced lupus (anti-dsDNA and anti-nuclear antibodies)
• Leukopenia, aplastic anaemia
• Optic neuritis
• Live vaccination contraindicated
  ► Inhibit patient's ability to form immunity to disease
  
  Examples: Etanercept, Infliximab, Adalimumab, Golimumab

Front 11

Describe biological DMARDs (IL-6 signalling inhibitors)

Back 11

Tocilizumab

M.O.A

• Humanized chimeric mAb IgG1 directed against IL-6R alpha chain
  
  
• Prevents binding of IL-6 to IL-6R alpha and IL-6 signalling
  
  Adverse effects
• Hyperlipidaemia
• Infections
• Skin eruptions
• Stomatitis
• Fever
• Neutropenia

Front 12

Describe biological DMARDs (B-cell depletion)

Back 12

Rituximab

M.O.A

• Humanised chimeric mAb IgG1 directed against CD20 on premature and mature B cells
  
  
• Depletes CD20+ B cells, blocks antigen presentation and auto-antibody & cytokine levels
  
  Adverse effects
• Rash on first dose
• Respiratory infection in COPD