Pharmacology - OA and RA

Question 1

What are the therapeutic options for OA?

Answer 1

1. Pain relief +/- anti-inflammatory
   - Paracetamol
   - NSAIDs (non-selective and COX-2)
   Corticosteroids
2. Symptomatic slow-acting drugs for OA (SYSADOA)
   - Intra-articular hyaluronic acid
   - for shock absorption, traumatic energy dissipation, lubrication

Question 2

Which compartment of the immune system is implicated in RA?

Answer 2

Mainly: B and T cells
Less: Phagocytes

Question 3

What do the immune cells do when they are activated in RA?

Answer 3

Proliferation + Cytokine production + Adhesion & Trafficking

Question 4

What cytokines are involved in the pathogenesis of RA?

Answer 4

[Main] IL-1, IL-6, TNF

JAK-STAT
- IL-2, IL-6, IL-12, IL-15,
- IFN-alpha, IFN-gamma

Question 5

Compare amongst the csDMARD agents.

Answer 5

Methotrexate -> 1st line
Hydroxychloroquine -> best tolerated
Ciclosporin

Question 6

Compare the targets amongst the bDMARDs.

Answer 6

[Anti-TNF mAb] infliximab, adalimumab, etanercept;
[IL-1R] antagonist: anakinra;
[Anti-IL6 receptor mAb] Tocilizumab;
[Anti-CTLA4Ig] abatacept;
[Anti-CD20] rituximab;

Question 7

[MoA] Methotrexate

Answer 7

[Major MoA] inhibition of ATIC leading to increased adenosine levels.
[Minor MoA] inhibition of dihydrofolate reductase and thymidylate synthetase.

Results in:
- increased extracellular adenosine level -> activation of adenosine A2a receptor -> Anti-Inflammatory
- Antiproliferative effects on T cells + inhibition of Macrophage functions
- Decrease in pro-inflammatory cytokines, adhesion molecules, chemotaxis, phagocytosis.

Question 8

[Side Effects] Methotrexate

Answer 8

N/V
Mouth and GI ulcers
Hair thinning

[^Mgmt] Folic / Folinic acid taken 12-24 hr after methotrexate.

Leukopenia
Hepatic fibrosis
Pneumonitis

Question 9

[Side Effects] JAK inhibitors

Answer 9

• Cytopenia -> immunosuppression -> opportunistic infections
• Anaemia (affects JAK2 activation by erythropoietin)
• Hyperlipidemia

Caution: do NOT combine w/ biological DMARDs.

Question 10

[MoA] Sulfasalazine

Answer 10

• Metabolized to sulfapyridine (active) + 5-ASA
• Mechanism in the gut microflora
• Decreased IgA and IgM rheumatoid factors
• T and B cells: suppressed
• Macrophages: suppressed
• Decrease in inflammatory cytokines

Question 11

[MoA] Leflunomide

Answer 11

• Rapid conversion to active metabolite Teriflunomide
• Dihydroorotate dehydrogenase: inhibited
• Decrease in pyrimidine synthesis and growth arrest at G1 phase
• T cell: proliferation inhibited
• B cell: autoantibody production inhibited
• NF-kB activation pathway: inhibited

Question 12

Unique feature of Leflunomide:

Answer 12

Is Teratogenic.
Long t1/2 -> take Colestyramine to wash-out Leflunomide before attempting pregnancy.

If not, should not get pregnant <2 years after last dose.

Question 13

[MoA] Hydroxychloroquine

Answer 13

• Reduced MHC Class II expression and antigen-presentation.
• Reduced TNF and IL-1, and cartilage resorption.
• Antioxidant activity.

Question 14

[Side Effects] Sulfasalazine

Answer 14

[Unique]
Haemolytic anaemia
Neutropenia
Reversible infertility in men

N/V
Headache
Rash

Question 15

[Side Effects] Leflunomide

Answer 15

[Unique]
Teratogenic
Weight gain

Diarrhoea
Elevation of liver enzymes
Alopecia

Question 16

[Side Effects] Hydroxychloroquine

Answer 16

[Unique]
Ocular toxicity

N/V
Stomach pain
Dizziness
Hair loss

Question 17

[Side Effects] TNF blockers

Answer 17

Respiratory / skin infection
Increased risk of lymphoma
Optic neuritis
Exacerbation of multiple sclerosis
Leukopenia
Aplastic anemia

Question 18

Contraindications and Cautions for TNF blockers

Answer 18

Live vaccination
Hepatitis B

[Monitoring] Screen for latent or active TB

Question 19

Name one prominent drug interaction of Tocilizumab (IL-6Ralpha inhibitor).

Answer 19

Decreased IL-6 activity -> increased expression of CYP450 enzymes (3A4, 1A2, 2C9)