Gout Flashcards
Pathophysiology
More males than femlaes
Monosodium Urate crystals- tophi
Imbalance in synthesis, breakdown, excretion
Peripheral joints- low temp, increased acidity in synovial fluid
Hyperuricaemia: obesity, diabetes, hypertension
10% gout- enzyme deficiency, glycogen storage disease, myeloproliferative disease
Purine Metabolism
Synthesis: De Novo or Salvage
PRPP Levels: determine DN synthesis- activator and substrate of Amido PRT
Increase De Novo: inc. purine turnover, inc. plasma uric acid
Increase Slavage: dec. DN, dec. plasma uric acid
Stages of Gout
Asymptomatic Hyperuricaemia- No treatment
Acute Gout- NSAIDs, Colchicine, Glucocorticoids(Prednisone)- Pain Big Toe
Intercritical phase- No treatment
Chronic gout- Allopurinol, Probenecid, Sulfinpyrazone- Tophi, recurrent
Inflammation in a gouty joint
Recognition of Monosodium Urate by TOLLR Phagocytosis Inflammasome activation IL-1Beta release Signal Transduction and Gene Activation IL8 release Neutrophil recruitment- IL-1Beta released again
Management of Acute Gout
Reduce pain and inflammation
NSAIDS- Ibuprofen or Indomethacin
Inhibit COX and inhibit TXA and PG synthesis
May abort acute attack if given early
SE: GI bleeding
Avoid low dose aspirin- precipitate attack by dec. renal clearance
Colchicine
Binds tubulin- inhibits polymerisation and formation of microtubules
Inhibits neutrophil activation by attenuating inflammatory response
Dec. Trafficking of particles to lysosomes
Dec. Release of chemotactic factor
Dec. Mobility and adhesion of neutrophils
Dec. Tyrosine phosphorylation of neutrophil proteins- dec. LYB4 synth
Colchicine SEs and use
Diarrhoea
Myelosuppression
Co-administered initially with drugs that alter urate homeostasis to avoid precipitating an acute attack
Colchicine Drug Interactions
Enterohepatic recirculation by liver MDR protein
Cyclosporin and tacrolimus- nephrotoxic
Reducing GFR and drug clearance
Allopurinol
For over producers
Competitively binds Xanthine Oxidase
Active metabolite- Oxypurinol( via Xanthine Oxidase)
Prevents molybdenum from intercomverting between +4 and +6
This freezes enzyme
Disrupts urate homeostasis-not for acute- Give with Colchicine or NSAID
SJ Syndrome and DRESS
Allopurinol Interaction
6MP active metabolite in cancer drugs
Azathioprine converted to 6MP to thiouric acid for excretion
Oxypurinol inhibits XO which catalyses last reaction
Uricosuric Agents
For under secretors
Probenecid
Increase uric acid secretion by inhibiting reabsorption in PCT
Via URAT1 & OAT1?
Lowers plasma urate, dissolving crystals and reversing deposition
SE: Urate stones- Calcium citrate makes more alkali
Agents that enhance Metabolism
Uricases- Pegloticase
Enzyme that oxidises uric acid to allantoin (easily excreted)
Use: tumour lysis syndrome (chemotherapy) to prevent kidney damage
IV
COX1 and COX2
Most NSAIDs are non-selective
Meloxicam relatively COX2 at lower doses
Rheumatoid Arthritis Goals
Relieve pain and inflammation
Prevent joint dysfunction
Preserve functional ability
Rheumatoid Arthritis Treatment
NSAIDs and analgesics
DMARDS
DMARDS (azothiaprine and methotrexate)
Cyclosporin, steroids, cyclophosphamide
NSAIDs Inhibition
Irreversible- Apsirin
Competitive-Ibuprofen
Reversible non-competitive- paracetamol traps free radicals and interferes with hydroperoxidases
Aspirin replaced by NSAIDS which are less toxic and longer acting
DMARDs
MOA unclear: long term depressive effect on inflammatory responses altering long term outcome and bone damage progression Slow onset: weeks- months Choice base on risk/benefit Usually sulphasalazine or methotrexate Regular monitoring for SE
Sulphasalazine
Most common DMARD in UK
5-ASA: free radical scavenger linked to sulphapyridine
Poorly absorbed orally- cleaved to active component by colonic bacteria
Sulphapyridine may reduce NK Cell activity
May cause acute haemolysis in G6PDH deficiency
Gold Salts
Accumulate in marrow, liver, spleen
Impair macrophage function and cytokine activity
Supresses phagocytosis and lysosomal enzyme activity
Inhibits PG synthesis and complement activation
Sodium aurothiomalate (IM), Aurofin (Oral)
Aurofin less efficacious and less toxic- more GI SE
Methotrexate- Immunosuppressant
Folic acid antagonist- dec. inflam cells in synovium reducing joint erosion
Teratogenic
Reversibly inhibits dihydrofolate reductase
Cumulative doses >1.5g (2yr)- liver toxicity: diabetics, alcoholics, obese
Decrease intra THF levels: cessation of De Novo synthesis
Leflunomide- Immunosuppressant
Undergoes biotransformation to teriflunomide
Inhibits dihydroorate dehydrogenase
Prevents pyrimidine synthesis targeting lymphocyte proliferation
Inhibits osteoclast production
Azothiopine- Immunosuppressant
Cleaved non-enzymatically by glutathine to 6-MP
Slow conversion favours immunosuppression
6-MP converted to T-IMP: Inhibits enzymes converting IMP to AMP and GMP
Inhibits DNA and RNA synthesis, energy storage and cell signalling
Inactivated by XO to 6-thiouric acid- caution Allopurinol
SE: bone marrow suppression, leukopenia
Cyclosporine
Peptide antibiotic
Normal: Antig bind Th receptor, inc. Ca, stimulate calcineurin, dephos NFAT, enhance transcription of IL2
Cyclosporin binds cyclophilin inhibiting calcineurin and dec. transcription of IL2 and IL2 receptors and T Cell activation
For refractory RA
SE Nephrotoxicity: Inc. TGFbeta synthesis of ECM
Etanercept- TNFa Inhibitor
Extracellular portion of human TNF fused to Fc of human IgG1
Soluble dimer
Prevents access of TNFa/b to target tissue
Recombinant DNA technology
