Drug Treatment of Gout Flashcards
What is gout?
An inflammatory arthritis caused by uric acid
What causes gout?
Genetic in origin causing raised uric acid levels.
What joints are commonly affected by gout?
Any joint (can be poly-articular)
Pedagra is gout of the big toe.
How does gout change over time?
it progresses more and more if not treated. It is a serious disease with functional disability.
How do uric acid levels rise to cause gout?
They must rise above 0.42 mmol/L (in men) or 0.36mmol/L in women.
Derived from:
Diet (~1/3)
Endogenous biosynthesis (~2/3)
It is the final product of purine metabolism in humans and eliminated by kidneys (2/3) and GI tract (1/3)
Uric acid is a weak organic acid and is poorly soluble at acidic pH and low temperature meaning it will precipitate in joints.
Why does uric acid cause the pain of gout?
Urate crystals deposit in peripheral joints and peri-articular tissues resulting in gout
Does hyperuricaemia always lead to gout?
No, there is hyperuricaemia in only about 10% of people with gout.
Uric acid may not be high in acute gout.
How is uric acid produced from endogenous biosynthesis?
Purines are converted into hypoxanthine
Hypoxanthine is converted into xanthine which is then converted into uric acid. (Both steps are done via the enzyme xanthine oxidase)
How is uric acid eliminated?
Humans don’t have uricase/urate oxidase. Instead they depend on renal + gut excretion.
How is uric acid excreted in the kidneys?
100% of uric acid that passes through the glomerulus is filtered through. However it is reabsorbed by GLUT9 (on basolateral membrane) and URAT1 (on apical membrane)
6 - 10% is then secreted in distal proximal tubule so a net loss of ~10% uric acid is the result
How is excretion different in people with gout to other people?
90% of hyperuricaemics undersecrete uric acid
What happens in gout?
Chronic hyperuricaemia (don’t have to be at time of diagnosis)
Supersaturation of body tissues with urate crystals
Formation of monosodium urate crystals in and around joints
Unidentified triggers cause shedding of crystals into the joint.
Crystals evoke an inflammatory response. (Kinin, complement and plasmin, neutrophilic infiltration which engulf crystals, release of toxic oxygen metabolites, tissue lysis and release of proteolytic enzymes)
How is gout diagnosed?`
Urate crystals in synovial fluid
Why is gout diagnosis levels increasing in the population?
Ageing population
Obesity
Sweet soft drink consumption
What are the dietary risks that lead to gout?
Sugary drinks, beer, fructose, and spirits are high risk.
Coffee, dairy products, vitamin C reduce risk
What are the risk factors for gout?
Genetic - Polygenic (urate transporter mutations)
Gender - Males are 3x more likely than females to develop gout.
Hypertension increases risk
Metabolic syndrome
Chronic renal failure
Transplantation - kidney and heart -> drugs
Drugs - thiazide diuretics, low dose aspirin, cyclosporin
Hyperuricaemia is an independent risk factor for CVD and metabolic syndrome
What is the aetiology of gout?
Purine nucleotides are converted into uric acid via xanthine oxidase.
Some is excreted via intestine and the rest via kidneys (secretion)
This condition is most commonly associated with a decrease in renal excretion in distal proximal tubule. (~90%) alcohol, obesity, fructose, and renal failure
Also associated with too much causative foods (Alcohol, meat, seafood) or too much purine turnover (caused by alcohol, fructose, BMI, and tumours)
What does coffee and vitamin C do to uric acid?
Coffee decreases uric acid formation and increases renal excretion
VitC increases renal excretion
Why does urate precipitate in joints?
The cause is unknown at this stage
What are the 2 clinical phases of gout?
Preclinical - crystal deposits increase in joint tissues for years then finally crystals shed into joint. (asymptomatic)
2 clinical =
Intermittent attacks of acute gout - no symptoms between attacks
Chronic tophaceous gout - if inadequately treated (visible deposits)
What is the most important feature to consider with acute gout?
It is rapid onset and can flare up overnight. (very painful and most common in the metatarsophalangeal joint of the big toe (1st joint)
What other symptoms are associated with gout?
Fever
Poly-articular
Self-limiting
What are tophi? What can they do to surrounding structures?
Large crystal deposits on extensor surfaces (fingers, hands, elbows, tendons, and ear)
These deposits can cause erosion of neighbouring joints leading to restricted movement and deformity.
What are the renal complications that can result from chronic gout? Also any other systemic disorders that can arise?
Can cause kidney stones and renal tissue deposits which lead to chronic renal failure.
It is also expected to contribute to CVD.
How is acute gout treated?
Pain relief (NSAIDS -> colchicine)
Glucocorticoids (especially if intra-articular and not septic)
Maintain long term treatment for chronic gout.
When newly diagnosed it is advisable to start urate-lowering therapies at lowest dose and titrate up slowly.
What is colchicine? What is its mechanism of action?
Ancient remedy from the autumn crocus.
It is a “keep in pocket” medication
Mechanism of action is not fully understood but binds to tubulin which stops MT assembly:
Cell division
Neutrophil motility
Decreases chemokine production
Inflammatory cell recruitment stops.
How is colchicine absorbed?
It is rapidly absorbed orally
Where does colchicine concentrate and get excreted?
Concentrates in WBCs
Excretion is hepatobiliary (10 - 20% renal)
What does colchicine do?
Good pain relief within 12 - 24 hours
Use analgesia while waiting for relief
What are the side effects and potential complications associated with taking colchicine? What are the DDIs?
It is toxic and causes vomiting and diarrhoea. It has a narrow therapeutic window.
Can result in a rare severe toxicity -> muscle damage, myelo-suppression, multiple organ failure
Do not describe if kidney or liver function is poor due to renal function.
DDIs - CYP3A4 & P-gp inhibitors
What are the DDIs of colchicine?
CY3A4 & P-gp inhibitors:
Antibiotics (erythromycin, clarithromycin)
Ca2+ channel blockers - verapamil, diltiazem
Cyclosporin, grapefruit juice
How has colchicine dosing changed?
It is now a low dose regimen
What precautions are given to patients prescribed colchicine?
Patients are advised not to eat/drink grapefruit
To stop if they have any signs of Nausea, vomiting, and diarrhoea
Making sure patient understands these 2 points.
How is chronic gout treated non-pharmacologically and pharmacologically?
Make lifestyle changes: Diet, alcohol and weight loss.
Drug therapy (Xanthine oxidase inhibitors, Uricase agents, Uricosuric agents)
What is the aim of chronic gout treatment?
To reduce serum uric acid
When should chronic gout be treated?
At the start of the first acute attack because this ensures better capture/compliance
What is xanthine oxidase? What drug inhibits it?
The enzyme that converts hypoxanthine into xanthine and then into uric acid.
Allopurinol inhibits this pathway. (competitive inhibitor) then gets converted into alloxanthin/oxypurinol which non-competitively inhibits xanthine oxidise.
How is allopurinol best prescribed due to method of absorbtion?
Well absorbed orally
What is the half life of allopurinol?
2 - 3 hours but its metabolite is 18 - 30 hours so only needs to be taken once a day.
How should allopurinol be prescribed?
Low does initially then increase by 100mg every 2 - 5/52 until SUA is 0.36mmol/L
Dose is maintained when target SUA is achieved.
Decrease doses in renal failure
Give prophylactic treatment (NSAIDs or colchicine) until target SUA is reached to prevent acute flares.
What are the adverse effects of using allopurinol?
GI side effects
Drug reaction rash with eosinophilia and systemic symptoms (DRESS) and if rash is severe - Stevens johnson syndrome/TEN (SCAR) - it is rare but potentially fatal. Monitor carefully this can be avoided if started low dose.
Who is at highest risk from adverse effects when using allopurinol?
East Asian with the IILA-B*5801 allele means very high risk. These people should be tested by PCR.
Instead give them febuxostat
What are some dangerous drug interactions to consider with allopurinol use?
Mercaptopurine and azanthioprine
Allopurinol increases their side effects dramatically
What is mercaptopurine?
Anti-metabolic chemotherapy agent that blocks DNA synthesis
What is azathioprine?
Azathioprine is a pro -drug immunosuppressant
What is febuxostat?
A non-purine selective inhibitor of XO.
Not a purine analogue
It is a replacement for allopurinol that is more expensive and only used in the people incapable of using allopurinol.
Where is febuxostat metabolised?
Mainly in the liver making it useful in patients with renal impairment or those who do not respond to allopurinol
What do uricosuric agents do?
Block urate re-uptake in the Proximal Tubule so this means patient must drink a lot of water.
What blocks the effect of uricosuric agents?
Effect is blocked by low dose aspirin
How should uricosuric agents be used?
Add to other therapies when SUA is too high.
What are uricase agents?
Converts uric acid to allantoin which rapidly drops serum uric acid levels which makes it useful for removing tophi.
Why can’t uricase agents be used for a long time?
IV only and short half life
Also issue with allergies
