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PHA332 > Gout Therapeutics > Flashcards

Gout Therapeutics Flashcards

1
Q

What is Gout/ crystal induced arthritis ?

A
  • Gout is the persistent raised level of Uric acid (urate) in the plasma, leads to the crystal formation in the joints.

-the main source of plasma uric acid is catabolism of nuclei acid purine bases guanine and adenine.

-painful inflammation within the joints

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2
Q

What are the properties of uric acid?

A
  • relatively insoluble in water, increase in uric acid will lead to crystal formation, thus meaning that uric acid coming out of solution and precipitating into joints.
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3
Q

Where is the most common site to find gout ?

A

The big toe

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4
Q

What are the risk factors associated with gout ?

A

Modifiable risk factors:
- diet ( purine rich foods e.g. seafoods, red meat etc)
-obesity

Non-modifiable risk factors:
-family history
-age
-sex (males at higher risk)
-racial background (African Americans more at risk, possibly due to the higher risk of CKD and hypertension) and china and Filipino
-medical condition
-medication
- obesity, BMI and cholesterol levels
-diet e.g alcohol, red meat and seafood

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5
Q

Why are people who suffer with hypertension, diabetes and diuretic use more likely to be at risk for gout ?

A

This refers to the fluid levels changing within the body, therefore more precipitation of crystals in the joints.

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6
Q

What foods are high in purines and how does this affect a patient who is consuming these foods?

A

-Foods high in purines are alcohols, red meat, sea food etc
-uric acid is the waste product of purines.

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7
Q

What foods help to prevent gout, and how do they work?

A

-vegetables and protein
-diary
Coffee
-vitamin c
-Cherries

They increase the body’s ability to decrease the uric acid levels within the body.

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8
Q

What are the important genes that are associated with gout?

A

Gout is the build up of uric acid in the body, the body excretes this acid through the kidneys.
1. SLC22A12- this gene encodes for the urate transporter 1, which is found on the brush border of proximal tubules.

2.SLCA9- this encodes for GLUT9- a urate uniporter.

3.SLC17A1-this encodes for NPT1 transporter

  1. ATP- binding cassette G2 ABCG2, this is a multi drug transporter in renal tubules and in the intestines, that excretes urate.

If there is any mutations in these genes it can lead to over reabsorption of uric acid.

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9
Q

Where does uric acid come from?

A

-Uric acid is the end product of purine nuclei acid degradation
-xanthine oxidase is an enzyme used to produce uric acid, inhibition of this would stop the production of uric acid and gout.

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10
Q

How dopes the purine metabolism process work?

A

-Adenine and guanine are both metabolised through the same pathway
-deamination occurs of Adenine
-ribose 5-p removal
-both these purines are converted into xanthine
-final conversion is to uric acid

IN HUMANS, ONLY EXCRETE LOW LEVELS OF URIC ACID THROUGH THE KIDNEYS, AND THE METABOLISM STOPS HERE.
WE HAVE LOW LEVELS OF URATE OXIDASE OR NONE AT ALL.

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11
Q

How do animals further metabolise uric acid?

A

-animals require to conserve water, so they metabolise uric acid and secrete it as a paste

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12
Q

What are the 2 genetically inherited genes ?

A

-Hypoxyanthine-guanine-phosphoribosyltransfase deficiency (HGPRT), if there is a deficiency in this there will be an increase in uric acid.
-5’ phosphoribosyl 1 pyrophospahte synthase deficiency (PRPP)

mutations in these genes can lead to gout

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13
Q

How does gout arise?

A

-Gout arises when monosodium urate crystals (MSU) deposit in cartilage in the joints

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14
Q

What is hyperuricaemia ?

A

HYPERURICAEMIA- this is the high levels of uric acid found in the blood.

Not all patients however develop gout when suffering with hyperuricaemia, but can if there is a >9mg/dL found in the blood.

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15
Q

What are the key stages to gout ?

A

-hyperuricaemia
-deposition of MSU crystals in the joints
-reduced solubility in the body
-nucleation
-crystal growth

LEADS TO THE INFLAMMATORY RESPONSE.

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16
Q

WHAT IS THE PATHOLOGICAL THRESHOLD OF URIC ACID IN THE BLOOD?

A
  • > 6.8mg/dL, if we get a higher value than this then a person is at risk of crystallisation in the joints.
17
Q

What factors effect solubility in the blood?

A
  • once you reach the >6.8mg/dL the the solubility decreases.
    -Synovial fluid (fluid within the joints) pH
    -water concentration, if the water concentration is low, then this can lead to precipitation.
    -electrolyte levels
    -proteoglycans/collagen levels
18
Q

Why is kidney function important in regards to uric acid excretion?

A

Good kidney health is important as uric acid is excreted via the kidneys, if there is bad kidney health in a patient then they are unlikely to fully excrete uric acid and it is remained in the body.

19
Q

What are the 4 major reasons to consider if one is diagnosed with gout?

A
  1. Accumulation of uric acid due to bad kidney function
  2. Patients on diuretics, water is getting excreted out of the body decreasing the water concentration, electrolyte levels etc, which can lead to MSU precipitation.

3.increased synthesis of uric acid due to cell turnover e.g. tumours
-break down of purines is a lot quicker, thus build up of uric acid

4.high dietary purine intake e.g. alcohol, red meat, sea food.

20
Q

How does gout present?

A
  1. Asymptomatic gout- hyperuricaemia, but no symptoms displayed.

2.acute gouty arthritis
-swollen joints with inflammation
-warmth and rednesss
-uric acid in the joint
-gout flares

3.chronic tophaceous gout
-after 10 years
-occurrence of tophi, lumps on the fingers

21
Q

What is tophi?

A

This is the region of chronic foreign body granulomatous response surrounding collections of MSU crystals.

-in other words, they are beginning to now stick to the surrounding tissues etc around the joint.

22
Q

How to diagnosis gout?

A

-physical observation
-x ray or ultra sounds
-lab tests e.g.serum uric acid, CRP c reactive protein, ESR (how quickly red blood cells will sediment)
-CVD and renal tests

GOLD STANDARD -MSU CRYSTAL DETECTION FROM THE SYNOVIAL FLUID

23
Q

How do we treat patients suffering with gout?

A

Lifestyle modifications:
-cut down on foods high in uric acid
-weight loss programme
- increase physical activity

Prophylactic treatment:
-xanthine oxidase inhibitors
-uricosuric drugs
-uricases

Symptomatic treatment:
-colchicine
-corticosteroids
-NSAIDs

24
Q

How do we treat ACUTE gout?

A

RICE:
-rest
-ice
-compression
-elevation

NSAIDs:
-diclofenac, naproxen, indomethacin, piroxicam with PPIs if necessary.

COX2 inhibitors:
-etoicoxib

Corticosteroids:
-prednisolone

25
Q

What is second line treatment in gout if the previous mentioned medications do not work?

A

COLCHICINE (max 6mg) especially if NSAIDs are contra indicated.

26
Q

How does COLCHICINE work ?

A

-it prevents microtubule assembly and disrupts the inflammasome and neutrophil activation. Stops inflammatory

-prevents microtubule based inflammatory cells chemotaxis (movement of these chemicals), prevents production of leukotrienes and cytokines and phagocytosis impacting pain and inflammation.
Slows down the production of prostaglandins,leukotrienes etc, limiting and reducing pain.

-when taking this drug thus a lowering of inflammation and pain
-does not effect serum uric acid concentration.

27
Q

What is first line treatment when we want to decrease serum uric acid levels and how does the following drug work?

A

ALLOPURINOL

  • it inhibits xanthine oxidase, which in turns stops the overall production of uric acid
    -slowed down production
    -so now these levels in the nobody can be excreted by the kidneys at a much faster rate
    -increases the more soluble precursors - xanthine and hypoxanthine.
    -Used long term.
28
Q

What is the pharmacology of allopurinol?

A

-orally given
-half life = 2-3hrs, the active metabolite alloxanthine has a half life’s of 18-30hrs
-really excreted

SIDE EFFECTS:
-GI disturbances
-allergic reactions
-Steven Johnson’s syndrome but is rare.

29
Q

Why don’t we give allopurinol during an acute attack?

A

Used as a longer term therapy
- this is because allopurinol is seemed to increase pain levels
-instability of the joints

If given combine with a NSAIDs or treat the pain and inflammation.

30
Q

What do we give if allopurinol is not tolerated?

A

FEBUXOSTAT

  • This is a xanthine oxidase inhibitor as well
31
Q

What are uricosuric agents?

A

THIRD LINE DRUGS
-these are drugs that increase the uric acid excretion by direct action on the renal tubules.
- Can be given with NSAIDs

WORKS ON BOTH URAT1 AND GLUT9, BLOCK THESE SO THEREFORE NOP REABSORPTION OF URIC ACID CAN TAKE PLACE BUT THEREFORE EXCRETED.

32
Q

Give examples of uricosuric drugs?

A
  1. Probenecid
    2.benzobromarone -potent but reports of liver damage
  2. Lesinurad- works on the urat1 , and inhibits it so that therefore more uric acid is excreted.
33
Q

What are IL1 biologics?

A

-binds to IL1 receptor
-to stop the inflammatory process and pain process
-decrease in pain.
USED IN PATIENTS WORK CANNOT USE NSAIDs OR COLCHICINE

34
Q

What is rasburicase?

A

-This is a preparation containing enzyme uric acid oxidase
- used in aggressive treatments of gout if all other treatments have failed.
-oxidises uric acid and converts it to Alantonin, thus more soluble, and can be excreted.
- it is IV administrated

35
Q

Why does a patient have to be careful with aspirin?

A

Increases uric acid concentration in the blood

36
Q

What heart medication can contribute to gout?

A

-ace inhibitors
-beta blockers
-diuretics

37
Q

What MHRA warnings are associated with FEBUXOSTAT?

A

-Hypersensitivity
-increased risk of cardiovascular related death in patients with CV disease

PHA332 (25 decks)

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