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E. Bones and Joints Drugs > 1. Drugs used for arthritic disorders > Flashcards

1. Drugs used for arthritic disorders Flashcards

1
Q

Drugs for osteoarthritis (OA)

A

Primarily symptomatic
1. Pain relief and/or anti-inflammatory: Paracetamol, Non‐selective NSAIDs (e.g., diclofenac), COX‐2 inhibitor (celecoxib), corticosteroids

  1. Symptomatic slow-acting drugs for OA (SYSDOA): Intra‐articular hyaluronic acid (HA)
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2
Q

MOA of Intra-articular hyaluronic acid (HA)

A
  1. Large glycosaminglycan (naturally in synovial fluid)
  2. Shock absorption, traumatic energy dissipation, protective coating of cartilage, lubrication, reduces pain & stiffness
  3. Induces biosynthesis of HA & extracellular matrix
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3
Q

Commonly used supplements for OA

A

chondroitin sulphate and glucosamine

BUT there is inadequate or inconsistent evidence

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4
Q

Drugs for Gouty arthritis

A

Acute Gouty Arthritis (Anti‐inflammatory Agents)

  1. Nonselective NSAIDs (e.g., naproxen, indometacin)
  2. COX‐2 selective NSAIDs (e.g., celecoxib)
  3. Glucocorticoids (e.g., prednisolone)
  4. Colchicine

Prevention of Gouty Episode (Urate‐Lowering Therapy, ULT)

  1. Xanthine Oxidase Inhibitors (XOI)
  2. Uricosuric Agents
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5
Q

MOA of NSAIDs in acute gouty attack

A

They inhibits production of prostaglandins and urate crystal phagocytosis

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6
Q

Contraindication with NSAIDs in acute gouty attack

A

low dose of aspirin, salicylates (anti‐uricosuric actions)

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7
Q

Examples of NSAIDs used in acute gouty attack

A
  1. Non‐selective COX inhibitors: naproxen, indometacin

2. Selective COX‐2 inhibitors: celecoxib

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8
Q

Example of glucocorticoid used in acute gouty attack

A

Prednisolone (oral or intra‐articular injection)

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9
Q

MOA of colchicine

A
  1. binds to tubulin
  2. prevent tubulin polymerization into microtubules
  3. inhibits leukocyte migration and phagocytosis
  4. inhibits leukotriene B4 (LTB4) and prostaglandin (PG) production

Relieve pain and inflammation in acute gouty attack within 24‐36 hours

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10
Q

Side effects of colchicine

A

diarrhoea, nausea & vomiting, abdominal pain, muscle weakness, unusual bleeding, pale lips, and change in urine amount

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11
Q

Drugs contraindicated in acute gouty attack

A
  1. Uric acid synthesis inhibitors → decrease the uric acid conc. in the plasma → change the uric acid conc. gradient from the joint to plasma → more uric acid mobilisation out of the joint and into the plasma → make ongoing acute gouty attack worse
  2. Uricosuric agents → increase uric acid excretion via the kidneys (on top of the normal uric acid excretion from gouty attack) → formation of uric acid kidney stones
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12
Q

Examples of uric acid synthesis inhibitors

A
  1. Allopurinol (1st-line)

2. Febuxostat (2nd-line)

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13
Q

MOA of uric acid synthesis inhibitors

A
  1. Anti‐hyperuricemic agents

2. ↓ Uric Acid Production by inhibiting xanthine oxidase

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14
Q

Indications for uric acid synthesis inhibitors

A
  1. debilitating gout attacks
  2. chronic erosive arthritis
  3. urate nephrolithiasis (kidney stone)
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15
Q

Adverse effects of uric acid synthesis inhibitors

A

Warning: Allopurinol hypersensitivity syndrome (AHS)
‐ Severe cutaneous adverse reaction (SCAR)
‐ Risk factors: renal impaired – creatinine clearance <60ml/min, thiazide therapy, HLA‐B *58:01 genotype

Side effects: skin rash, nausea & vomiting, diarrhea, fever, sore throat, stomach pain, dark urine, jaundice

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16
Q

Example of uricosuric agent

A

Solute carrier family 2 & 22 inhibitor: Probenecid

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17
Q

MOA of uricosuric agent

A
  1. inhibits proximal tubule anion transport
  2. inhibits uric acid re‐absorption
  3. increases uric acid excretion
18
Q

Indications for uricosuric agents

A
  1. when allopurinol is contraindicated in tophaceous gout
  2. in increasingly frequent gouty attack
  3. start 2‐3 weeks after an acute attack
19
Q

Adverse effects of uricosuric agents

A

Precautions:
‐ take plenty of fluid to minimize renal stone formation
‐ keep urine pH >6.0 by administration of alkaline (e.g., potassium citrate)

Side effects:
‐ Nausea & vomiting, painful urination, lower back pain, allergic reactions, rash

20
Q

Drug treatment for rheumatoid arthritis

A

Anti‐inflammatory Agents:

  1. NSAIDs ‐ short‐term relief of pain & stiffness (+ proton pump inhibitor to ↓ GI side effects)
  2. Corticosteroids ‐ “bridging” anti‐inflammatory therapy

Conventional synthetic DMARD (csDMARD):

  1. Methotrexate (standard of care) +
  2. Sulfasalazine
  3. Leflunomide
  4. Hydroxychloroquine (best tolerated)
  5. Ciclosporin

Targetted synthetic DMARD (tsDMARD):
Tofacitinib / Baricitinib

Biologic DMARD (bDMARD)

  1. Anti‐TNF mAb (e.g., infliximab, adalimumab, etanercept)
  2. IL‐1R antagonist (e.g., anakinra)
  3. Anti‐CTLA4Ig (e.g., abatacept)
  4. Anti‐CD20 (e.g., rituximab)
  5. Anti‐IL‐6 receptor mAb (e.g., tocilizumab)
21
Q

MOA of methotrexate

A
  1. Major Action:
    • Increased adenosine levels due to 5‐aminoimidazole‐4‐carboxamide ribonucleotide (AICAR) transformylase/ IMP cyclohydrolase (ATIC) inhibition
  2. Minor Action:
    • Inhibits dihydrofolate reductase and thymidylate synthetase
  3. Overall Effects:
    • Increase in extracellular adenosine level and activation of adenosine A2a receptor
    • Anti‐proliferative effects on T cells and inhibition of macrophage functions
    • Decrease in pro‐inflammatory cytokines, adhesion molecules, chemotaxis and phagocytosis
22
Q

Side effects of methotrexate

A
  1. Nausea & vomiting (N/V), mouth and GI ulcers, hair thinning
    • Keep side effects to a minimum: Concomitant folic acid or folinic acid given 12‐24 hr after methotrexate decreases toxicity
  2. Leukopenia, hepatic fibrosis, pneumonitis
23
Q

MOA of sulfasalazine

A
  1. Metabolized to sulfapyridine (active) + 5‐aminosalicylic acid
  2. Mechanism of action not known but poorly absorbed so may be mediated by effect on gut microflora and leads to:
    • Decreased IgA and IgM rheumatoid factors
    • Suppression of T and B cells, and macrophages
    • Decrease in inflammatory cytokines e.g., IL‐1β, TNF and IL‐6
24
Q

Side effects of sulfasalazine

A

N/V, headache, rash, haemolytic anaemia, neutropenia, reversible infertility in men

25
Q

MOA of leflunomide

A
  1. Rapidly converted to active metabolite teriflunomide (A77‐1726)
  2. Inhibits dihydroorotate dehydrogenase
  3. Decrease in pyrimidine synthesis and growth arrest at G1 phase
  4. Inhibits T cell proliferation and B cell autoantibody production
  5. Inhibits NF‐κB activation pro‐inflammatory pathway
26
Q

Side effects of leflunomide

A
  1. Warning: Very long half‐life (detectable even years after last dosing)
    • Colestyramine (bile salt binding resin) wash‐out (e.g., before pregnancy)
  2. Side effects: diarrhoea, elevation of liver enzymes, alopecia, weight gain, teratogenic
27
Q

MOA of chloroquine and hydroxychloroquine

A
  • Anti‐malarial agents
  • Effective anti‐inflammatory agents in RA (least potent DMARD)
  • Reduced MHC Class II expression and antigen‐presentation
  • Reduced TNF‐α and IL‐1, and cartilage resorption
  • Antioxidant activity
28
Q

Adverse effects of chloroquine and hydroxychloroquine

A

Nausea & vomiting, stomach pain, dizziness, hair loss, ocular toxicity

29
Q

Examples of tsDMARDs

A

Jakinibs e.g., tofacitinib

30
Q

MOA of tsDMARDs

A
  • Janus kinase (JAK) pathway inhibitor

* Blocks cytokine production by blocking JAK/STAT‐activation of gene transcription

31
Q

Adverse effects of tsDMARDs

A
  • Cytopenia including neutrophils, lymphocytes, platelets and natural killer cells
  • Immunosuppression resulting opportunistic infections [increased risk of herpes zoster infection (especially in Asian population)]
  • Anaemia (affects JAK2 activitation by erythropoietin)
  • Hyperlipidemia: increases in total, LDL and HDL cholesterol and triglycerides
  • Do NOT combine with biological DMARDs
32
Q

Examples of TNF blockers (bDMARDs)

A

infliximab, adalimumab, etanercept

33
Q

Example of IL-1R antagonist (bDMARDs)

A

anakinra

34
Q

Example of Anti‐CTLA4Ig (bDMARDs)

A

abatacept

35
Q

Examples of Anti-CD20 (bDMARDs)

A

rituximab

36
Q

Example of Anti-IL-6 receptor mAb (bDMARDs)

A

tocilizumab

37
Q

Side effects of TNF blockers (bDMARDs)

A

Respiratory infection and skin infection, increased risk of lymphoma, optic neuritis, exacerbation of multiple sclerosis, leukopenia, aplastic anemia,

38
Q

Side effects of anakinra

A

Infections, injection site reactions

39
Q

Side effects of abatacept

A

Respiratory infection in COPD, ↑ lymphoma incidence

40
Q

Side effects of rituximab

A

Rash in first dose, respiratory infection in COPD

41
Q

Side effects of tocilizumab

A

Infections, skin eruptions, stomatitis, fever, neutropenia, increase in ALT/AST, hyperlipidaemia, interacts with CYP450 34A, 1A2 or 2C9 substrates

Tocilizumab metabolised by proteolytic enzymes. But IL-6 decease expression of these CYP450 enzymes, so tocilizumab increase expression

E. Bones and Joints Drugs (1 decks)

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