Exam 2 - Medchem 753, Delander Gout

Question 1

What is gout?

Answer 1

Inflammatory disease that results in urate crystals in joints and soft tissues

Question 2

What causes the formation of crystals in gout?

Answer 2

Crystals form due to improper handling of uric acid which causes a supersaturated solution of urate precipitating crystals

Question 3

How many people in the US are affected with Gout?

Answer 3

8 million (4% of population)

Question 4

What factors are associated w/or are aggravated by Gout?

Answer 4

Genetics (big)
Obesity (Surface area?)
Age (older worse)
Adult Males
Potmenopausal women
HTN
Diet (high purine or high fructose)

Question 5

What disease states might Gout be more prevalent in?

Answer 5

Lesch-Nyhan Syndrome
End Stage renal disease
Cancers w/ cell lysis
Major Organ Transplant

Question 6

What Drugs may induce or exacerbate the presence of Gout?

Answer 6

Thiazides (Diuretics) - compete for transporters
Low dose Aspirin
Niacin
Immune Suppressants
Cytotoxic agents causing cell lysis

Question 7

What is Lesch-Nyhan Syndrome?

Answer 7

A disease characterized by a lack of HGPRT which results in problems in the breakdown and removal of Urate. It is a Problem w/ Metabolic Process that some people have that does not have salvage pathway which results in higher amounts of Uric Acid and gout like symptoms.

Question 8

What are the disease stages of Gout?

Answer 8

Acute
Intermittent
Chronic

Question 9

When do Acute phases of Gout generally occur?

Answer 9

At night while asleep, while not moving, increased likelihood of crystalizing out due to things cooling down.

Question 10

What are the common characteristics of acute gout?

Answer 10

• Crystals form in joint(Very common in big toe)
• low grade fever
• typically resolves in 3-14 days
• May not have another attack for quite a while or ever
• Intense pain

Question 11

What are the common characteristics of intermittent gout?

Answer 11

• Acute attacks x2 or more per year

- Usually in more than one joint (not always toe)

Question 12

What are the common characteristics of chronic Gout?

Answer 12

Means that something is happening w/ disease state to cause other problems

• Start therapy
• Changes in renal
• permanent crystals setting in joints
• generally polyarticular (many joints)

Question 13

What affect does change in diet have on disease state?

Answer 13

Generally very minimal effect

Question 14

Where do Purines come from?

Answer 14

1. Our cells, constantly breaking down and forming it

2. Food

Question 15

What is the enzyme animals have to break down Uric Acid?

Answer 15

Uricase (urate oxidase) which breaks down urate into Allantoin

Question 16

What animal species do not contain Uricase?

Answer 16

Humans, Apes and Dalmations (dog)

Question 17

What percentage of Uric Acid enters the Proximal tubule from glomerulus?

Answer 17

100%

Question 18

What percentage of Uric Acid is reabsorbed by glomerular filtration?

Answer 18

98-100%

Question 19

Due to secretion and reabsorption of Uric Acid, what percentage of Uric Acid is actually excreted in Urine?

Answer 19

8-12%

Question 20

Due to secretion and reabsorption of Uric Acid, what percentage of Uric Acid is actually excreted in Urine?

Answer 20

8-12%

increasing is current area of drug research

Question 21

What are Inflammasomes?

Answer 21

When there are high levels of Uric Acid in plasma, the uric acid cystallize and are phagocytized and form these, which release IL-1b, which activates a huge inflammatory response.

Question 22

How much Uric Acid is the “magic number”? At what level is treatment usually started?

Answer 22

~7mg/dL

Question 23

What are the chronic problems of gout that we are worried about with managing Gout?

Answer 23

• Renal - Nephrolithiasis (stones) and Interstitial Nephritis
• Arthritic - Deposition of Tophi, erosion of Cartilage and bone, loss of function
• Metabolic - associated w/ metabolic syndrome, stroke and other CVD

Question 24

What is the gold standard in diagnosing Gout? What else is used?

Answer 24

Visualization of Uric Acid Crystals in aspirated synovial fluid

Differential Diagnosis by using colchicine to treat

Question 25

What are the treatment goals of Acute Gout?

Answer 25

Resolve inflammatory process rapidly

Question 26

What are the treatment goals of intermittent/chronic Gout?

Answer 26

Decrease Uric Acid so we don't have long term problems of effects New Guidelines state we don't try to control serum level, we treat to control symptoms.

Question 27

What medication has traditionally been the go to therapy for Acute flares of Gout? Why is it no longer? What is the first line according to guidelines now?

Answer 27

Colchicine, Price Steroid then NSAID

Question 28

Colchicine 1. MOA 2. Dosing 3. SE 4. Considerations

Answer 28

1. Decrease Microtubule formation, which limits chemotaxis 2. (1.2mg, prn 0.6mg an hour later) effective for 36hrs (1.2mg/day generally for 14 days) 3. GI upset (25%), Muscle Weakness (inc w/ statins), Bone Marrow Suppression (penias) 4. Price, Dose adjustments w/ Hepatic failure, inhibits 3A4 & PGP

Question 29

What other drug classes are often prescribed for acute Gout flares?

Answer 29

``` NSAIDS Steroids IL-1 Antagonists (off label) Adrenocorticotropic hormone (ACTH) Opioids (?) ```

Question 30

When using NSAIDS to control Gout: | what Med do you not want to use, what is traditionally used, what is common now?

Answer 30

- Don't use Salicylates (Acetaminophen no effect, not an NSAID) - Historically use Indomethacin - Now Naprosyn or Naproxen common - Any can be used

Question 31

When using Steroids to control gout, | What is most common? dosing?

Answer 31

Prednisilone, 0.5mg/kg (~35mg/day) orally for 5 days, although can be given injection

Question 32

Interleukin 1 antagonists | Anakinra and Canakinumab

Answer 32

- Not a lot known SE wise because they are rarely used, - Thought to stop Interleukin-1b from causing inflammasome response - Expensive as fuck

Question 33

Adrenocorticotropic Hormone in treatment of Gout

Answer 33

Increases availability of cortisol (endogenous steroid)

Question 34

Opioids in treatment of Gout?

Answer 34

Only treats the symptoms, covers up the pain.

Question 35

What behavioral changes can be adopted?

Answer 35

- Weight loss - Diet (avoid foods high in purines, adequately hydrated) - Watch for Drugs that may aggravate Historically doesn't change a ton and is rarely adequate by itself

Question 36

When is chronic treatment generally pursued?

Answer 36

Increase in Uric Acid levels above 7mg/dL AND: - When patient is fed up with acute flares - >2 flares per year - Tophi present - Kidney disease/presence of stones

Question 37

When you pursue Chronic therapy, what is a common side effect?

Answer 37

Increased incidence of acute flares within 6months of therapy

Question 38

Does pH have anything to do with acute flare ups?

Answer 38

Delander, doubtful, but it may increase amount of stones

Question 39

When you pursue Chronic therapy, what is a common side effect?

Answer 39

Increased incidence of acute flares within 6months of therapy (prophylaxis of acute attacks required)

Question 40

Does pH have anything to do with acute flare ups?

Answer 40

Delander, doubtful, but it may increase amount of stones. Otherwise don't know

Question 41

What are common Xanthine Oxidase inhibitors?

Answer 41

Allopurinol | Febuxostat

Question 42

Allopurinol 1. MOA 2. Dosing 3. SE 4. Considerations

Answer 42

1. Is a purine and uric acid analog inhibitor, inhibits the Xanthine Oxidase, decreasing the amount of uric acid produced. 2. initially 100mg/day, increase by 100mg weekly, usually 300mg, max 800mg] 3. Rash, Fever, GI, malaise, itching 4. Hypersensitivity (Steven Johnson), DDI (Azathioprine & Mercaptopurine) 80% renal clearance (adjust renal impairment)

Question 43

How to minimize the side effects of allopurinol?

Answer 43

- slow titration of medication Hypersensitivity: - Limit use in HLA-B 5801 allele pts

Question 44

What populations more commonly express HLA-B 5801 allele?

Answer 44

Asians - Thai - Han Chinese (Taiwan) - Koreans

Question 45

What drugs should not be used alongside Allopurinol or Febuxostat?

Answer 45

Azathioprine | Mercaptopurine

Question 46

Febuxostat in the control of Gout 1. MOA 2. Dosing 3. SE 4. Considerations

Answer 46

1. Non-purine inhibitor, non-competitively inhibits Xanthine Oxidase to reduce amount of Uric Acid produced 2. 40mg/day up to 80mg/day, max 120mg 3. Rash, Fever, GI, malaise, itching 4. No hypersentivity rxn, Primarily Hepatic metabolism

Question 47

What uricosuric agents are used to control gout?

Answer 47

Probenecid | Lisinurad

Question 48

Probenecid 1. MOA 2. Dosing 3. SE 4. Considerations

Answer 48

1. Relatively non specific transport inhibitor (facilitate excretion) 2. usually 250mg bid, up to 2000mg 3. Rash; GI 4. DDI (Beta lactams, Methotrexate); Contraindicated in low CrCl (<50mL/min), those with G6P dehydrogenase deficiency

Question 49

What populations are generally deficient for G6P dehydrogenase?

Answer 49

Mediterraneans | Blacks (10%)

Question 50

Lisinuard 1. MOA 2. Dosing 3. SE 4. Considerations

Answer 50

1. Inhibits Uric Acid Transporter 1 (URAT-1), reduces reabsorption from proximal tubule (facilitate excretion) 2. 200mg/day 3. Headache, Malaise, GERD 4. Renal Failure in monotherapy

Question 51

What Drug class must accompany the use of Lisinurad?

Answer 51

Xanthine Oxidase Inhibitors

Question 52

When using Uricosurics, what counseling point is of the utmost importance?

Answer 52

Adequate Hydration

Question 53

If Disease state does not respond to Xanthine Oxidase inhibitors or Uricosurics what is another option? Why is it not common?

Answer 53

Recombinate Uricase Expensive as fuck Exceedingly immunogenic

Question 54

Rasburicase and Pegloticase

Answer 54

Rasburicase (only available w/ infusion) | Pegloticase (Pegylated uricase in order to not have a huge immune response)