Joint Pain Flashcards
What are the classes of drugs to treat RA?
Anti-Inflammatory Agents (NSAIDS & Corticosteroids)
Conventional Synthetic DMARDs - Methotrexate, Sulfasalazine, Leflunomide, Hydroxychloroquine, Ciclosporin
Targeted Synthetic DMARDs - Tofacitinib
Biologic DMARDs - Infliximab, Anakinra, Abatacept, Rituximab, Tocilizumab
What is methotrexate?
A folic acid analog
What is so good about methotrexate?
Long-term efficacy, acceptable toxicity & low cost, associated with significantly lower mortality
How is methotrexate administered?
Oral, Subcutaneous Injection, Intra-muscular
How can efficiacy of methotrexate be increased?
Administer with other sDMARDs
What is the major action of methotrexate?
Inhibition of AICAR & ATIC, resulting in increased adenosine levels; then via adenosine receptors result in an anti-inflammatory actions
- down regulation of pro-inflammatory cytokines
- inhibition of apoptosis
- inhibition of polymorph chemotaxis
What is the minor action of methotrexate?
Inhibits dihydrofolate reductase and thymidylate synthetase, resulting in decreased DNA methylation, pyramidine and purine synthesis
What is the significance of the minor action of methotrexate?
Causes adverse effects (hair loss & nausea)
What are the side effects of methotrexate?
Nausea & Vomitting, GI Ulcers, Hair thinning
Leukopenia, Hepatic Fibrosis, Pneumonitis
How can the side effects of methotrexate be kept to a minimum?
Concomitant folic acid or folinic acid given 12-24h after methotrexate decreases toxicity
Why can’t folate be given to rescue methotrexate toxicity?
Folate does not efficiently rescue to toxicity due to depletion of N5, N10-methylene-FH4 as dihydrofolate reductase is inhibited
What is the mechanism of action of sulfasalazine?
Poorly absorbed, mediated by effect on gut microflora, leading to:
- Decreased IgA and IgM rheumatoid factors
- suppression of T cells. B cells & macrophages
- decrease in inflammatory cytokines IL-1beta, TNF, IL6
What are the side effects if sulfasalazine?
Nausea & Vomitting, Rash, Hemolytic Anemia, Neutropenia, Reversible infertility in men
What is the mechanism of action of leflunomide?
Rapidly converted to active metabolite teriflunomide, inhibiting dihydroorotate dehydrogenase
- decrease in pyrimidine synthesis and growth arrest at G1 phase
- inhibits T cell proliferation and B cell autoantibody production
- inhibits NF-kB activation pro-inflammatory
What are the side effects of leflunomide?
- Diarrhoae
- Elevation of liver enzymes
- Alopecia
- Weight gain
- Teratogenic
What are precautions to note with regards to leflunomide?
- Very long half life (detectable even years after last dosing)
- Colestyramine (bile salt binding) wash out (e.g. before pregnancy)
What are chloroquine and hydroxychloroquine also used for?
Anti-malarial drugs
What is the mechanism of action for chloroquine and hydroxychloroquine?
- Reduced MHC class 2 expression and antigen presentation
- Reduced TNF-alpha and IL-1 and cartilage resorption
- Antioxidant Activity
What is the side effects of chloroquine and hydroxychloroquine?
- Nausea & Vomitting
- Stomach Pain
- Dizziness
- Hair loss
- Ocular Toxicity
What is the mechanism of action for tofacitinib?
Janus kinase (JAK) pathway non-selective inhibitor - blocks cytokine production by blocking JAK-STAT activation of gene transcription
What other disease can tofacitinib be used for?
Psoriatic Arthritis
How may tofacitinib be prescribed?
- Combined with methotrexate for moderate to severe RA
- Monotherapy in cases of intolerance to methotrexate or methotrexate and multiple bDMARD0refractory active RA
What are side effects of tofacitinib?
- Cytopenia including neutrophils, lymphocytes, platelets and natural killer cells
- Immunosuppression resulting in opportunistic infections [increased risk of herpes zoster infection esp in asian population]
- Anemia (affects JAK2 activation by EPO)
- Hyperlipidemia: Increases in total, LDL, and HDL cholesterol and triglycerides
What is a precaution in taking tofacitinib?
Do not combine it with biological DMARDs: risk of too great immunosuppression resulting in increased risk of opportunistic infections
What are the biological DMARDs that target TNF?
- Infliximab
- Adalimumab
- Golimumab
- Etanercept
What construct are the biological DMARDs that target TNF?
- Infliximab – Chimeric
- Adalimumab – Human mAb
- Golimumab – Human mAb
- Etanarcept – Recombinant Fusion Protein (Decoy Soluble TNF-IgG1 Receptor that intercepts TNF)
What are the half lives of anti-TNF biologics?
- Infliximab – 8-9 days
- Adalimumab – 14 days
- Golimumab – 12 days
- Etanercept – 70h
When are anti-TNF biologics prescribed?
For RA patients that do not respond well to sDMARD therapies
What is the method of administration for anti-TNF biologics?
- Infliximab – IV
- Adalimumab – Subcutaneous
- Etanercept – Subcutaenous
What are the side effects of anti-TNF biologics?
Respiratory and Skin infection
Increased risk of lymphoma
3. optic neuritis
4. exacerbation of multiple sclerosis
5. leukopenia
6. aplastic anemia
What are the contraindications for prescribing anti-TNF biologics?
Live vaccination, hep b
What must be monitored for when prescribing Anti-TNF biologics?
Latent or active TB
What is an IL1 antagonist?
Anakira
What is the mechanism of action of anakira?
Binds to IL-1 receptor and blocks signalling
What are side effects of anakira?
- Infections
- Injection site reactions
What is the disadvantage of anakira?
Less effective than anti-TNF bDMARDs
What is an IL6 receptor antagonist?
Tocilizumab
What is the mechanism of action of tocilizumab?
Humanized mAb directed at IL-6R chain; prevents binding of IL-6 to IL6-Ralpha and prevents homodimerisation of IL-6Rbeta signalling
What are the side effects of tocilizumab?
Infections, Skin eruptions, stomatitis, fever. neutropenia, increase in ALT/AST, hyperlipidemia, interacts with CYP450 enzymes 34A, 1A2, 2C9 (metabolised by proteolytic enzymes, but IL6 normally decreases expression fo CYP450 enzymes, so as tocilizumab decreases IL6 these CYP450 enzymes increase)
What is the mechanism of action of abatacept?
Recombinant fusion protein with CTLA-4-FcIgG1
Binds to CD80 & CD86 and prevents CD28 activation
T-cell therapy
What are the side effects of abatacept?
Respiratory infection in COPD
Increased lymphoma incidence
What is the mechanism of action of Rituximab?
Chimeric mAb IgG1 directed at CD20 on pre- and mature B cells
Depletes CD20+ B cells
B cell therapy
Blocks antigen presentation, autoantibody and cytokines
What are side effects of rituximab?
Rash in first dose
Respiratory infection in COPD
