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Flashcards in Gout Deck (26):
1

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

2

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

3

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

4

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

5

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

6

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

7

Colchicine SEs and use

Diarrhoea
Myelosuppression
Co-administered initially with drugs that alter urate homeostasis to avoid precipitating an acute attack

8

Colchicine Drug Interactions

Enterohepatic recirculation by liver MDR protein
Cyclosporin and tacrolimus- nephrotoxic
Reducing GFR and drug clearance

9

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

10

Allopurinol Interaction

6MP active metabolite in cancer drugs
Azathioprine converted to 6MP to thiouric acid for excretion
Oxypurinol inhibits XO which catalyses last reaction

11

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

12

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

13

COX1 and COX2

Most NSAIDs are non-selective
Meloxicam relatively COX2 at lower doses

14

Rheumatoid Arthritis Goals

Relieve pain and inflammation
Prevent joint dysfunction
Preserve functional ability

15

Rheumatoid Arthritis Treatment

NSAIDs and analgesics
DMARDS
DMARDS (azothiaprine and methotrexate)
Cyclosporin, steroids, cyclophosphamide

16

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

17

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

18

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

19

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

20

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

21

Leflunomide- Immunosuppressant

Undergoes biotransformation to teriflunomide
Inhibits dihydroorate dehydrogenase
Prevents pyrimidine synthesis targeting lymphocyte proliferation
Inhibits osteoclast production

22

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

23

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

24

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

25

Infliximab- TNFa Inhibitor

Partially humanised MAb against TNFa
Vh and Vl derived from mouse antihuman sequences
Remainder from human sequences
Reduces development of neutralising Ab to infliximab

26

RA Pathophysiology

TNFa and IL1 are key
They activate osteoclasts
Cause bone degredation