Joint Pain Pharm Flashcards
What are the 3 drugs used for the treatment of OA?
Pain relief/anti-inflammatory
1) Paracetamol
2) NSAIDs (eg. diclofenac, celecoxib)
3) Corticosteroids
Symptomatic slow-acting drugs for OA (SYSADOA)
4) Intra-articular hyaluronic acid
What is the moa of Intra-articular hyaluronic acid used as a SYSADOA?
Naturally occurring large glycosaminoglycan
a) shock absorption, traumatic energy dissipation, protective coating of cartilage, lubrication,
→ ↓pain and stiff ness
b) Induces biosynthesis of more hyaluronic acid and ECM
True or false: In addition to paracetamol, NSAIDs, corticosteroids, and HA, OTC supplements such as chondroitin sulphate and glucosamine have been proven to aid in treating osteoarthitis.
False.
Inadequate/inconsistent evidence despite being popular as supplements
What are the 3 primary targets of RA treatment?
1) Synovial tissues
2) Bone erosion
3) Joint deformity
What are 3 points for approaches to RA therapy?
1) Early diagnosis and treatment
2) Synthetic Disease-Modifying Anti-Rheumatic Drug (sDMARD) alone or in combination
3) Add biological DMARD targeted at TNF, IL-1R and IL-6
What are 3 therapeutic goals of RA?
1) Remission of joint symptoms
2) Return of full function
3) Maintenance of remission of DMARD therapy
What are 7 drugs used in the treatment of RA?
Anti-inflammatory agents:
1) NSAIDs
2) Corticosteroids
Conventional synthetic DMARD
3) Methotrexate
4) Sulfasalazine
5) Leflunomide
6) Hydroxychloroquine
7) Ciclosporin
Targeted synthetic DMARD
8) Tofacitinib/Baricitinib
Biologic DMARD
9) Anti-TNF mAB (eg. infliximab, adalimumab, etanercept)
10) IL-1R antagonist (eg. anakinra)
11) Anti-CTLA4Ig (eg. abatacept)
12) Anti-CD20 (eg. rituximab)
13) Anti-IL-6 receptor mAb (eg. Tocilizumab
What is the first-line choice DMARD therapy for RA?
Methotrexate (folic acid analog)
What is the moa of methotrexate in treating RA?
Major:
↑adenosine levels due to AICAR transformylase/ATIC inhibition
Minor:
Inhibits dihydrofolate reductase and thymidylate synthetase → ↓purine synthesis
Overall:
i) ↑extracellular adenosine and adenosine A2a receptor activation
ii) Anti-proliferative effect on T cells and inhibition of macrophage functions
iii) ↓pro-inflammatory cytokines, adhesion molecules. chemotaxis and phagocytosis
What are 5 AEs of methotrexate?
1) Nausea and vomiting
2) Mouth and GI ulcers
3) Hair thinning
4) Leukopenia
5) Hepatic fibrosis
6) Pneumonitis
How can the side effects of methotrexate (eg. nausea and vomiting) be minimised?
Concomitant folic acid or folinic acid given 12-24 hrs after methotrexate
What are the modes of administration of methotrexate?
1) Oral
2) SQ
3) IM
What is methotrexate often combined with for optimal effects in treating RA?
Other sDMARDs
(eg. hydroxychloroquine, ciclosporin, sulfasalazine, leflunomide)
Which is more effective at rescuing methotrexate toxicity, folate or folinic acid?
Folinic acid
- Folate cheaper but effect still limited by inhibition of dihydrofolate reductase inhibition
- Folininc acid converted to N5, N10-Methylene-FH4 → bypass dihydrofolate reductase activity → more effective at rescuing methotrexate toxicity
How does Sulfasalazine (csDMARD) help in treating RA?
Metabolised to sulfapyridine (active) + 5-aminosalicyclic acid →
i) ↓IgA and IgM rheumatoid factors
ii) Suppression of T and B cell and macrophages
iii) ↓inflammatory cytokines
What are 5 AEs in sulfasalazine (csDMARD)?
1) Nausea and vomiting
2) Headache
3) Rash
4) Haemolytic anaemia
5) Neutropenia
6) Reversible infertility in men
How does Leflunomide (csDMARD) help in treating RA?
Converted to teriflunomide (active) → inhibits dihydroorotate dehydrogenase → ↓ pyrimidine synthesis and growth arrest @ G1
i) inhibits T cell proliferation and B cell autoAb production
ii) inhibits NF-kB activation (pro-inflammatory pathway)
What are 4 AEs of Leflunomide (csDMARD)?
1) Diarrhoea
2) Elevation of liver enzymes
3) Alopecia
4) Weight gain
5) Teratogenic
How do chloroquine and hydroxychloroquine (csDMARD) help in treating RA?
Anti-inflammatory agents in RA:
i) ↓MHC class II exp. → ↓Ag presentation
ii) ↓TNF and IL-1 and cartilage resorption
iii) Antioxidant activity
What are 4 AEs of chloroquine and hydroxychloroquine?
1) Nausea and vomiting
2) Stomach pain
3) Dizziness
4) Hair loss
5) Ocular toxicity
What are 4 indications of tsDMARDs (JAKnibs) eg. tofacitinib?
1) Combined with methotrexate for moderate to severe RA
2) Monotherapy during methotrexate intolerance
3) Methotrexate + multiple bDMARD-refractive active RA
4) Psoriatic arthritis
What is the general moa of tsDMARDs (JAKnibs) eg. tofacitinib?
JAK pathway inhibitor → blocks cytokine production (via blocking of JAK/STAT-activation of gene transcription)
When is tsDMARDs (JAKnibs) eg. tofacitinib absolutely contraindicated for?
CANNOT combine with biological DMARDs
What are 4 AEs of tsDMARDs (JAKnibs) eg. tofacitinib?
1) Cytopenia (eg. neutrophils, platelets, NK cells, Lymphocytes)
2) Immunosuppression (eg. VZV infection)
3) Anaemia (affects JAK2 by EPO)
4) Hyperlipidemia
- ↑total, LDL, HDL cholesterol
- ↑TGs
What is the moa of Anakinra in treating RA?
Recombinant IL-1R antagonist SQ → block signalling
(less effective than anti-TNF bDMARDS)
What are 2 AEs of Anakinra?
1) Infections
2) Injection site reaction
What is the moa of Tocilizumab in treating RA?
Humanised mAb against IL-6R (α-chain) → prevents binding and homodimerisation of IL-6Rß signalling
What are 4 AEs of Tocilizumab?
1) Infections
2) Skin eruptions
3) Stomatitis
4) Fever
5) Neutropenia
6) ↑ALT/AST
7) HLD
8) ↓CYP450 exp.
What is the moa of Abatacept in treating RA?
Recombinant fusion protein with CTLA4-FclgG1
i) Binds to CD80 & CD86 → prevents CD28 activation
ii) T cell therapy (IV)
What are 2 AEs of Abatacept?
1) Respiratory infection in COPD
2) ↑Lymphoma incidence
What is the moa of Rituximab in treating RA?
Chimeric mAb IgG1 directed at CD20 on pre- and mature B cells →
i) Depletes CD20+ B cells
ii) B cell therapy (IV)
iii) Blocks Ag presentation
iv) ↓AutoAb and cytokines
What are 2 AEs of Rituximab?
1) Rash in first dose
2) Respiratory infection in COPD
What are 2 indications of TNF blockers used in the treatment of RA (eg. Adalimumab, Infliximab, Etanercept)?
1) RA px who do not respond well with sDMARD therapies
2) In combination with Methotrexate for optimal effects
What are 4 AEs of TNF blockers used in the treatment of RA (eg. Adalimumab, Infliximab, Etanercept)?
1) Respiratory and skin infections
2) ↑risk of lymphoma
3) Optic neuritis
4) Exacerbation of multiple sclerosis
5) Leukopenia
6) Aplastic anemia
What are 2 contraindications of TNF blockers used in the treatment of RA (eg. Adalimumab, Infliximab, Etanercept)?
1) Live vaccination
2) Hep B
What should be done for a px undergoing TNF blockers used in the treatment of RA (eg. Adalimumab, Infliximab, Etanercept)?
Screen for latent or active TB
How are the bDMARDs administered?
1) Anakinra (SQ)
2) Tocilizumab (SQ)
3) Abatacept (IV)
4) Rituximab (IV)
TNF signal blockers:
5) Infliximab (IV)
6) Adalimumab (SQ)
7) Golimumab (IV)
8) Etanercept (SQ)
What is the moa of Etanercept (bDMARD)?
TNF signal blocker:
Decoy TNFR2 receptor-IgG1 fusion protein intercepts TNF
Given that Leflunomide is teratogenic yet has a very long T1/2 (detectable even years after last dosing), what is given to “wash-out” the leflunomide in pregnant women?
Colestyramine
