Pharmacology of RA and Gout Drugs

Question 1

ADR of Allopurinol and Febuxostat

Answer 1

SCAR (SJS, TEN) HLA-B*58:01, Skin rash, N/V/D, stomach pain, fever, sore throat, dark urine, jaundice

Question 2

ADR of Colchicine

Answer 2

GI effect (N/V/D), muscle weakness, unusual bleed, pale lips, urine amount changes

Question 3

MOA and ADR of Probenecid

Answer 3

MOA: Uricosuric agent
- Inhibit proximal tubule anion transport
- Inhibit reabsorption and increase excretion

ADR: N/V, painful urination, lower back pain, allergy, rash

Question 4

MOA and ADR of Methotrexate

Answer 4

MOA:
1) AICAR (5-aminoimidazole-4-carboxamide ribonucleotide transformylase) / ATIC (IMP Cyclohydrolase) Inhibition → Adenosine A2a receptor activation
2) Dihydrofolate reductase and thymidylate synthetase Inhibition
3) Increased activation of adenosine A2a receptor; Anti-proliferative effect on T cell and macrophages; Reduced pro-inflammatory cytokines

ADR: N/V, Ulcers (Mouth, GI), Hair thinning, leukopenia, hepatic fibrosis, pneumonitis, myelosuppression, TENS, SJS

Question 5

Why are high doses of folate required for rescue therapy of MTX toxicity? Why is folinic acid or folinate more effective?

Answer 5

Folate does not efficiently rescue toxicity that results from depletion of N5, N10-Methylene FH4 as DHFR is inhibited

Rapid conversion of N5-formyl FH4 (Folinate) to N5, N10-Methylene FH4, bypassing the DHFR activity

Question 6

MOA and ADR of Sulfasalazine

Answer 6

MOA:
1. Reduced IgA and IgM RF
2. Suppression of T cell, B cell, macrophages
3. Reduced inflammatory cytokines

ADR:
N/V, headache, rash, hemolytic anemia, neutropenia, reversible infertility in men

Question 7

MOA and ADR of Leflunomide and the name of the active metabolite

Answer 7

Active metabolite: Teriflunomide

MOA:
1. Dihydroorotate dehydrogenase inhibition
2. Pyrimidine synthesis inhibition
3. Growth arrest at G1 phase
4. T cell anti-proliferation
5. B cell autoantibody production is reduced
6. NF-kB activated proinflammatory pathway inhibition

ADR: Diarrhea, LFT enzyme raised, Alopecia, weight gain, Teratogenic

Question 8

Leflunomide washout: Use what and why?

Answer 8

Colestyramine (Bile salt binding resin) before pregnancy (teratogenic) due to long half-life for years

Question 9

Hydroxychloroquine MOA and ADR

Answer 9

MOA:
1. Reduce MHC II expression
2. Reduce antigen presentation
3. Reduce TNF alpha and IL-1
4. Reduce cartilage resorption
5. Antioxidant

ADR:
N/V, stomach pain, dizzy, hair loss, ocular toxicity, myelosuppression

Question 10

Tofacitinib MOA and ADR

Answer 10

Janus Kinase Pathway Inhibition and thus cytokine gene transcription inhibition

ADR:
- Cytopenia (Neutrophil, Lymphocyte)
- Immunosuppression
- Anemia
- Hyperlipidemia

Question 11

Which bDMARDs target TNF-alpha, IL-1, IL-6, CD20 and CD28?

Answer 11

TNF-alpha: Adalimumab, Etanercept, Golimumab, Infliximab

IL-1: Anakinra

IL-6: Tocilizumab

CD20: Rituximab

CD28: Abatacept

Question 12

List the safety concerns for bDMARDs and tsDMARDs

Answer 12

• Injection site/infusion reactions: acute/delayed
• Myelosuppression: need to monitor CBC with WBC differentials & platelet count
• Infections: URTI, TB, hepatitis, opportunistic infections à pre-DMARD screening & Tx needed
• Malignancy risk: similar risks between bDMARD & tsDMARD - SDM
• Autoimmune diseases: SLE or lupus-like syndromes, demyelinating peripheral neuropathies
• Cardiovascular diseases: HF (avoid TNF-alpha inhibitors in NYHA class III & IV), HTN,
• Hepatic effects: Increased aminotransferase à monitor LFT
• Metabolic effects: Hyperlipidemia à monitor lipid panel
• Pulmonary diseases: Pulmonary toxicity à use with caution in interstitial disease
• Gastrointestinal perforation: esp with IL-6 inhibitors & JAK inhibitors (risk factors: diverticulitis, > 65yo, GC use, NSAID use) / also reported in Rituximab (ave onset ~ 6 days, range 1-77 days) à evaluate abdo pain or repeated vomiting
• Thrombosis: esp with JAK inhibitors & IL-6 inhibitors (avoid in patients w Hx of thrombotic events)