Anti-rheumatic drugs (DMARDs) Flashcards
List the relevant DMARDs used to treat RA
Methotrexate
Sulfasalazine
Gold compounds
Penicillamine
Chloroquine
What are the main targets (generally) for DMARDs?
Preventing antigen-presenting cells from activating T cells
Preventing IL-2 activation of TNF-alpha
Preventing induction of cytotoxic T cells
Preventing activation of B cells
Preventing production of autoimmune antibodies
Impairing IL-1 action
What is the MOA sulfasalazine?
Scavenging toxic oxygen metabolites produced by neutrophils
Inhibits T-cell proliferation and B-cell activation
Has a 5-aminosalicylic acid moeity that is a putative radical scavenger
What are some notable ADRs of sulfasalazine?
GI disturbances, malaise, headaches
Skin reactions (reversible)
*Impairs folic acid absorption
Blood dyscrasia
Anaphylactic type reactions
What is the MOA of gold compounds used in RA?
Unclear MOA = Auranofin (NOT AUROTHIOMALATE) inhibits induction of IL-1 and TNF-alpha
Helps ease pain and swelling, prevent progression of bone and joint disease
How do gold compounds react/behave in the body? (pk, accumulation?, excretion?)
Oral form = auranofin; IM = sodium aurothiomalate
Gradually concentrates in tissue (liver, synovial, kidney tubules, adrenal cortex, macrophages)
Renally excreted but remains in tissue
What are some notable ADRs of gold compounds?
skin rashes, mouth ulcers, flu-like sx
proteinuria, thrombocytopenia
Encephalopathy, peripheral neuropathy, hepatitis
What is the MOA penicillamine?
Dec immune response, IL-1 generation, and/or partly by an effect on collagen synth
Outline some key points of penicillamine pk (oral absorption? excretion?)
Only half of oral dose absorbed
Excreted in urine
Metal chelator, do not give w/ gold compounds
Appearance of what penicillamine ADRs should result in cessation of therapy?
Bone marrow disorders (e.g. leucopenia, aplastic anaemia)
Autoimmune reactions (e.g. thyroiditis, myasthenia gravis)
List some notable ADRs of penicillamine in RA
Occurs in 40% patients, dose dependent
Anorexia, fever, N/V, taste disturbances, rashes
Dose related thrombocytopenia
Which DMARD can cause ocular toxicity?
hydroxychloroquine
What is the MOA of methotrexate?
Inhibits dihydrofolate reductase –> prevent formation of active folate and addition of single carbon units to DNA base precursors
Impair B cells and T cells too
What are some notable ADRs of methotrexate?
Blood dyscrasia (some fatal) - folic acid may minimise
Liver cirrhosis
GI toxicity
Stomatitis
C/I in pregnancy
What is the MOA of azathioprine?
Metabolised to 6-mercaptopurine –> inhibits clonal proliferation during induction phase of the immune system by a cytotoxic action on dividing cells
What are the notable ADRs of azathioprine?
Depression of bone marrow
N/V, skin, eruption, mild hepatotoxicity
What is the MOA of leflunomide?
Relatively specific inhibitory effect on activated T cells
Its metabolite inhibits de novo synthesis of pyrimidines by inhibiting dihydroorotate dehydrogenase
List some notable points about leflunomide pk (circulation? oral activity?)
Orally active, well absorbed from GIT
Long plasma half
Active metabolite teriflunomide = undergo enterohepatic circulation
What are some notable ADRs of leflunomide?
Diarrhoea, alopecia
Raised liver enzymes (inc risk of hepatic failure)
Long half life = inc risk of cumulative tox
Foetal injury is used in preg
List the main anti-cytokine drugs used in RA
Infliximab, adalimumab
Etanercept
Anakinra
Basiliximab and daclizumab
What is the main target of infliximab and adalimumab?
Chimeric mouse/human monoclonal antibodies against TNF-alpha
What is the main target of etanercept?
TNF receptor fused to the Fc domain of human IgG molecule
What is the main target of anakinra?
IL-1 antagonist
What is the main target of basiliximab and daclizumab?
monoclonal antibodies against alpha chain of the IL-2 receptor
Outline some important facts about anticytokine pk (etanercept, inflix, adalim, anakinra)
Etanercept = subcut
Inflix = used w/ methotrexate, IV
Adalimumab = sc
Anakinra = sc daily
What are some notable ADRs of the anticytokine drugs used in RA?
May precipitate latent disease or encourage opportunistic infections –> due to immunosuppressive properties (impact on immune cells)
Etanercept = Blood dyscrasias and demyelinating CNS disorders
What is the MOA of tofacitinib?
Inhibits JAK protein –> prevents phosphorylation of STAT –> prevents translocation of STAT into the nucleus and activation of gene transcription
downregulates cytokine production
What are some notable ADRs of tofacitinib?
Immune syst suppression (screen for TB. hep)
Elevated cholesterol
GI (diarrhoea, bowel perforation)
Lymphoma and other malignancies
