1. Drugs used for arthritic disorders Flashcards
Drugs for osteoarthritis (OA)
Primarily symptomatic
1. Pain relief and/or anti-inflammatory: Paracetamol, Non‐selective NSAIDs (e.g., diclofenac), COX‐2 inhibitor (celecoxib), corticosteroids
- Symptomatic slow-acting drugs for OA (SYSDOA): Intra‐articular hyaluronic acid (HA)
MOA of Intra-articular hyaluronic acid (HA)
- Large glycosaminglycan (naturally in synovial fluid)
- Shock absorption, traumatic energy dissipation, protective coating of cartilage, lubrication, reduces pain & stiffness
- Induces biosynthesis of HA & extracellular matrix
Commonly used supplements for OA
chondroitin sulphate and glucosamine
BUT there is inadequate or inconsistent evidence
Drugs for Gouty arthritis
Acute Gouty Arthritis (Anti‐inflammatory Agents)
- Nonselective NSAIDs (e.g., naproxen, indometacin)
- COX‐2 selective NSAIDs (e.g., celecoxib)
- Glucocorticoids (e.g., prednisolone)
- Colchicine
Prevention of Gouty Episode (Urate‐Lowering Therapy, ULT)
- Xanthine Oxidase Inhibitors (XOI)
- Uricosuric Agents
MOA of NSAIDs in acute gouty attack
They inhibits production of prostaglandins and urate crystal phagocytosis
Contraindication with NSAIDs in acute gouty attack
low dose of aspirin, salicylates (anti‐uricosuric actions)
Examples of NSAIDs used in acute gouty attack
- Non‐selective COX inhibitors: naproxen, indometacin
2. Selective COX‐2 inhibitors: celecoxib
Example of glucocorticoid used in acute gouty attack
Prednisolone (oral or intra‐articular injection)
MOA of colchicine
- binds to tubulin
- prevent tubulin polymerization into microtubules
- inhibits leukocyte migration and phagocytosis
- inhibits leukotriene B4 (LTB4) and prostaglandin (PG) production
Relieve pain and inflammation in acute gouty attack within 24‐36 hours
Side effects of colchicine
diarrhoea, nausea & vomiting, abdominal pain, muscle weakness, unusual bleeding, pale lips, and change in urine amount
Drugs contraindicated in acute gouty attack
- 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
- 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
Examples of uric acid synthesis inhibitors
- Allopurinol (1st-line)
2. Febuxostat (2nd-line)
MOA of uric acid synthesis inhibitors
- Anti‐hyperuricemic agents
2. ↓ Uric Acid Production by inhibiting xanthine oxidase
Indications for uric acid synthesis inhibitors
- debilitating gout attacks
- chronic erosive arthritis
- urate nephrolithiasis (kidney stone)
Adverse effects of uric acid synthesis inhibitors
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
Example of uricosuric agent
Solute carrier family 2 & 22 inhibitor: Probenecid
MOA of uricosuric agent
- inhibits proximal tubule anion transport
- inhibits uric acid re‐absorption
- increases uric acid excretion
Indications for uricosuric agents
- when allopurinol is contraindicated in tophaceous gout
- in increasingly frequent gouty attack
- start 2‐3 weeks after an acute attack
Adverse effects of uricosuric agents
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
Drug treatment for rheumatoid arthritis
Anti‐inflammatory Agents:
- NSAIDs ‐ short‐term relief of pain & stiffness (+ proton pump inhibitor to ↓ GI side effects)
- Corticosteroids ‐ “bridging” anti‐inflammatory therapy
Conventional synthetic DMARD (csDMARD):
- Methotrexate (standard of care) +
- Sulfasalazine
- Leflunomide
- Hydroxychloroquine (best tolerated)
- Ciclosporin
Targetted synthetic DMARD (tsDMARD):
Tofacitinib / Baricitinib
Biologic DMARD (bDMARD)
- Anti‐TNF mAb (e.g., infliximab, adalimumab, etanercept)
- IL‐1R antagonist (e.g., anakinra)
- Anti‐CTLA4Ig (e.g., abatacept)
- Anti‐CD20 (e.g., rituximab)
- Anti‐IL‐6 receptor mAb (e.g., tocilizumab)
MOA of methotrexate
- Major Action:
• Increased adenosine levels due to 5‐aminoimidazole‐4‐carboxamide ribonucleotide (AICAR) transformylase/ IMP cyclohydrolase (ATIC) inhibition - Minor Action:
• Inhibits dihydrofolate reductase and thymidylate synthetase - 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
Side effects of methotrexate
- 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 - Leukopenia, hepatic fibrosis, pneumonitis
MOA of sulfasalazine
- Metabolized to sulfapyridine (active) + 5‐aminosalicylic acid
- 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
Side effects of sulfasalazine
N/V, headache, rash, haemolytic anaemia, neutropenia, reversible infertility in men
