Pharmacology of Gout Drugs

Question 1

Does gout occur in one or many joints

Answer 1

Usually just one joint and is episodic

Question 2

What are the most common joints affected by gout

Answer 2

Big toe joint
Lesser toe joint
Ankle and the knee

Question 3

What is the other name for Pseudogout

Answer 3

CPPD - calcium pyrophosphate deposition disease

Question 4

What is the main difference between pseudogout and gout

Answer 4

Pseudogout affects larger joints than gout (such as the knee)
Form of arthritis characterised by sudden, painful swelling in one or more joints.

Question 5

Treatment for pseudogout

Answer 5

NSAIDs
Colchicine
Corticosteroids

Question 6

When does inflammation occur in gout?

Answer 6

When monosodium urate crystals are deposited in the tissues

Question 7

How does hyperuricemia occur in patients with gout

Answer 7

under excretion rather than overproduction of urate

Question 8

What are purines (adenine and guanine) degraded to in the body?

Answer 8

Uric acid

Question 9

What are pyrimidines (cytosine, thymine, uracil) degraded to in the body

Answer 9

Urea

Question 10

Why does purine degradation matter

Answer 10

1. Excessive build up of uric acid leads to gout
2. Adenosine deaminase deficiency in humans leads to Severe Combined Immunodeficiency disease

Question 11

Why does having two or more daily servings of fizzy drinks increase the risk of gout by 85%

Answer 11

1. Fructose metabolism by the liver increases the sequential breakdown of ATP to AMP to IMP to inosine which are precursors to uric acid. Plasma uric acid levels rise within minutes.
2. Fructose enhances uric acid reabsorption.

Question 12

What is sucrose?

Answer 12

A disaccharide of glucose and fructose
Broken down into these monosaccharides in the liver.

Question 13

How are glucose and fructose transported across the brush border cell membrane

Answer 13

by SGLT1 and GLUT5

Question 14

Where are the highest levels of fructokinase?

Answer 14

The liver

Question 15

Which foods are linked to gout?

Answer 15

Offal
Oily fish
Seafood
Alcohol - especially beer

Question 16

Name the 3 classes of anti-gout drugs and their MOA

Answer 16

• Xanthine Oxidase inhibitors - inhibit the production of urate
• Uricosurics - Normalise renal excretion of urate
• Recombinant uricases - Cataluse the conversion of urate to the more water soluble and readily excreted allantoin (recombinant uricases)

Question 17

How do MSU crystals activate the inflammatory response

Answer 17

• MSU crystals form in the body
• These trigger TLR-2 and TLR-4
• This stimulates phagocytosis of MSU crystals and NFkB mediated cell activation
• In the cytosol, MSU crystals activate inflammasome formation
• Inflammasome formation processes pro-IL-B into mature IL1-B
• Activation of the endothelium by IL-1B increases trafficking of neutrophils to the inflammatory site

Question 18

How does colchicine operate to treat gout at nM concentrations?

Answer 18

• modulate the expression of adhesion proteins on endothelial cells
• inhibit IL-1 induced L-selectin expression
• modulate cytokine release
• diminish neutrophil chemotaxis to cytokines

Question 19

What are microtubules formed from?

Answer 19

heterodimers of alpha and beta tubulin heterodimers

Question 20

Where does colchicine bind to?

Answer 20

beta tubulin of microtubules

Question 21

Name 3 anti-IL1 treatments

Answer 21

• Anakinra
• Rilonacept
• Canakinumab

Question 22

How does anakinra work?

Answer 22

Recombinant IL-1 receptor antagonists - inhibits the binding of IL1-a and IL-1b to the IL-1R
Short t1/2
Used in RA

Question 23

How does rilonacept work

Answer 23

fusion protein acting as a suitable decoy receptor which binds IL-1a and IL-1b - approved for a few autoimmune rare syndromes

Question 24

How does Canakinumab work?

Answer 24

fully human anti-IL1 monoclonal antibody
only IL-1 treatment licensed for gout

Question 25

When is Canakinumab licensed for gout?

Answer 25

For patients in whom NSAIDs and colchicine are contraindicated, are not tolerated, do not provide an adequate response and in whom repeated courses of corticosteroids are not appropriate.

Question 26

Which 2 reactions does xanthine oxidase catalyse?

Answer 26

The conversion of Hypoxanthine to Xanthine
The conversion of Xanthine to Xanthine Oxidase
Therefore the inhibition of XO reduces not only the synthesis of uric acid, but also the production of its precursor

Question 27

When are XOi recommended and not recommended?

Answer 27

they are recommended as first line ULT in the majority of patients with normal renal function
XOi are not effective in treating an acute attack (may prolong it indefinitely if started during the acute episode)

Question 28

What is the active metabolite of Allopurinol?

Answer 28

Oxypurinol

Question 29

How does Oxypurinol work?

Answer 29

It irreversibly inhibits xanthine oxidase
It has a half life of > 1 day.
It keeps the Mo atom of the XO in the +4 oxidation state (preventing it from returning to a +6 oxidation state)
This keeps XO inactive and does not allow any further production of uric acid

Question 30

What is the half life of Allopurinol vs. Oxypurinol

Answer 30

Allopurinol - 1-2 hours
Oxypurinol - >1 day

Question 31

What are the most serious life-threatening illnesses that can develop from Allopurinol?

Answer 31

SCARs (severe cutaneous adverse reactions) including DRESS (drug hypersensitivity syndrome), SJS (Stevens- Johnson’s syndrome) and TEN (toxic epidermal necrolysis)

Question 32

How does allopurinol interact with azathioprine?

Answer 32

Azathioprine is metabolised to 6-mercaptopurine which in turn is inactivated by the action of xanthine oxidase- giving with allopurinol will lead to overdose of either drug - only 1/3 or 1/4 of azathioprine should be given

Question 33

How does allopurinol interact with capecitabine?

Answer 33

Capecitabine is metabolised to 5-FU which in turn inhibits thymidylate synthase. Allopurinol decreases the efficiency of 5-fu

Question 34

How does Allopurinol react with Didanosine?

Answer 34

Allopurinol increases plasma concentrations of didanosine - risk of toxicity

Question 35

What is the MOA of Febuxostat?

Answer 35

It is a non purine inhibitor of XO - blocks the access channel to the molybdenum-pterin active site of the enzyme

Question 36

When is Febuxostat recommended?

Answer 36

When allopurinol is contraindicated and/or not tolerated