Pharmacology of the Musculoskeletal system Flashcards

Question

Issues with bisphosphonates

Answer 1

* ADR * Osesophageal irritation (po) * Osteonecrosis of jaw (usually only with prolonged use) * Caution * Avoid with antacids and Ca2+ – reduced po absorption • Contraindications • Hypocalcaemia • Avoid if eGFR less than 35 mL/minute/1.73 m2 . • GI disease • Patients should report; any oral problems (see ADR); thigh/hip pain - possibility of atypical femoral fracture if excessive bone demineralization • Falling out of favour due to ADRs/ poor bioavailability and advances in therapy

Answer 2

* Most common joint disease * Affects at least one joint in 2/3 population over 75, usually weight bearing joints (hip, knee). Results from disorder of articular cartilage leading to loss of cartilage * Underlying bone exposed and remodelled new bone growth * loss of joint mobility * Treatment * Pain management with paracetamol, codeine, NSAIDS * New biological approaches being developed

Answer 3

* 1% of population, typically in 40-60 year olds * Autoimmune disease * systemic inflammation, may see inflammatory processes outside joints * Increased mortality due to cardiac disease (esp. ischaemic heart disease) * Wrist, shoulder, knee * Repeated remission and relapse, worsening at each relapse * Antigen * Unknown arthritogenic antigen induces self-perpetuating immune response * Exogenous, endogeous? * Autoantibodies to IgG and collagen, not clear these are causative * Genetic predisposition * linked to certain MHC alleles

Answer 4

* Infiltration and accumulation of CD4+ T cells in synovium * T cells release cytokines (e.g. TNF and IL-1) stimulating B cells (autoantibodies), recruit additional leukocytes eg neutrophils, * Macrophages – stimulating proliferation of synovial cells

Answer 5

* Proliferation of synovium cells; “hyperplasia” * Forms folds linked together by fibrin • Cells become invasive, form “pannus” • covering and destroying articular cartilage, tendons and joint capsule • Macrophages, recruited neutrophils and synovial cells release proteases, destroy proteins in cartilage and bone * Osteoclasts activated by RANKL (elevated in RA) degrade bone. * joint damage, destruction of joint capsule and tendons causes deformities

Answer 6

• Early treatment with Diseasemodifying anti-rheumatic drugs (DMARDs) • e.g. methotrexate; sulfasalazine; gold; hydroxychloroquine; ciclosporin • Joint replacement • Anti-TNFα drugs • Enteracept, infliximab, adalimumab

Answer 7

* Pain caused by crystals of sodium urate in joints * Sparingly soluble * 6.8 mg/L * Plasma concentration * 4-6 mg/L * Crystals can form in joints * Esp. great toe * Lower temp * Synovial fluid more acidic than plasma * Can form white/yellow lumps in skin “tophi” * Uric acid is product of purine metabolism * Renal secretion * 90% filtered reabsorbed by URAT1 transporter in kidneys

Answer 8

* Accumulation of uric acid leads to formation of sodium urate crystals in joints * Immune responses lead to acute/chronic inflammation

Answer 9

* Patients affected * with polymorphisms in genes regulating purine synthesis and degradation, URAT1 * Drugs which increase renal uric acid reabsorbtion (eg diuretics) * Purine rich diet (red meat) * Several stages * 1st phase: Asymptomatic, elevated urate * Acute gout: Sodium urate induces inflammation (“gouty arthritis”) * Very painful – therapy aims to control this * Intercritical phase * Asymptomatic, elevated urate * Chronic phase * Recurrent attacks, several joints affected * Therapy aims to modify urate metabolism and restore [urate]

Answer 10

* Used to treat pain & reduce inflammation in gout * Naproxen, Ibuprofen, diclofenac * See pain and analgesia lecture * Colchicine (see later) may be used if these are contraindicated

Answer 11

* Allopurinol * Used in chronic gout * Inhibits xanthine oxidase, increasing urinary secretion of hypoxanthine and xanthine * Reduced [urate] in plasma * ADR * Hypersensitivity, possibly developing to Stevens-Johnson syndrome in rare cases * Drug interactions * Affects metabolism of purine based drugs that are metabolized by xanthine oxidase * Mercaptopurine * Azathioprine * Inhibits metabolism of warfarin * Febuxostat * Recently licensed

Answer 12

* Indications * Used in chronic gout, sometimes in acute gout * Inhibits microtubule polymerization * Prevents intracellular transport (“trafficking”) mediated by microtubules * Inhibitors neutrophil inflammatory response * ↓ transport of phagocytosed urate crystals * ↓ synthesis and secretion of chemotactic factors particularly LTB4 * ↓ motility and adhesion * Pharmacokinetics * Excreted by PgP and undergoes enterohepatic recirculation * Metabolised by p450 3A4 ADR • GI disturbances • Diahorrea see PK • turnover of GI epithelial cells see mechanism • myelosuppression through inhibition of mitosis see mechanism • Peripheral neuropathy Caution Low therapeutic window Contraindications • Advanced renal failure (cannot be removed by haemodialysis) Drug interactions • P450 inhibitors • PgP inhibitors

Answer 13

* Neuromuscular blockers * principal use as adjunct to general anaesthesia * e.g. suxamethonium * See anaesthesia lecture * Myasthenia gravis * Auto-immune disease, antibodies to muscle nAChR * Causes muscle weakness * Potentiate activity of acetylcholine with acetylcholinesterase inhibitors e.g. pyridostigmine