Gout

Question 1

Gout

Answer 1

Inflammatory Arthritis
Purines (from diet / tissue breakdown) -> Uric Acid
Uric Acid - (uricase not in humans) -> allantoin

Question 2

Uric Acid Levels

Answer 2

Uric Acid (UA) is soluble at concentrations < 6.7 mg/dL
Crystals deposit in joints
• Phagocytosed triggering an immune response

Excess serum uric acid caused by:
• Overproduction of urate
• Underexcretion of urate

Question 3

*Gout and Disease States

Answer 3

Should Know

The following diseases promote hyperuricemia:
• Insulin resistance (DM)
• Hyperlipidemia
• Obesity
• Renal insufficiency/Chronic Kidney Disease
• Hypertension
• Organ transplantation
• CHF

Question 4

Diet and Gout - Hyperuricemic Foods

Answer 4

Meat (particularly organ meats)
Seafood
Beer and Liquor (particularly beer and spirits > wine)
Soft Drinks (high sugar)
Fructose (also high fructose corn syrup)

Question 5

Diet and Gout - Uricosuric Foods

Answer 5

Uricosuric = LOWER Uric acid levels

Coffee
Dairy
Vitamin C

Question 6

Medications and Gout - Hyperuricemic Agents

Answer 6

Thiazide Diuretics
Loop Diuretics
Nicotinic Acid
Aspirin (<1g/day)
Cyclosporine, Tacrolimus, Pyrazinamide, Levadopa, Ethambutol

Question 7

Medications and Gout - Uricosuric Agents

Answer 7

Uricosuric = Uric Acid LOWERING agents

Losartan
Fenofibrate

Question 8

Podagra

Answer 8

First metatarsophalangeal (Big toe) joint involvement most common

Question 9

Gout flare (attack)

Answer 9

Rapid onset (within 24 hours) of severe pain, erythema and swelling in a single or multiple joints

Podagra

Question 10

Tophi

Answer 10

Mass of urate deposits in bone, cartilage, joints or tissues

Question 11

Gout Diagnosis

Answer 11

Diagnosed by synovial fluid aspiration and identification of monosodium urate crystals (not routinely done in outpatient)
• Associated with a serum uric acid > 6.8 mg/dL
• However, serum uric acid may not be elevated in an acute attack
• Not all patients with hyperuricemia will develop gout
Flare/attack presentation generally confirms diagnosis - doesn’t require synovial fluid aspiration

Question 12

Acute Gout

Answer 12

Goals of therapy: Reduce pain and duration of attacks

Anti-inflammatory agents:
• NSAIDs
• Colchicine
• Corticosteroids
• Oral, intraarticular

Question 13

NSAIDs

Answer 13

COX inhibition
One not more efficacious than another
-Indomethacin, naproxen and sulindac have FDA approved labeling for gout
Timing of administration (<24 hours) more important to treatment success than choice of agent
Resolution of symptoms usually within 5-8 days of initiation

Avoid use in:
• Renal insufficiency/failure
• Bleeding disorders/anticoagulated patients
• Peptic ulcer disease
• CHF
• Older adults (≥75 years)

Question 14

Colchicine

Answer 14

MOA: inhibition of β-tubulin polymerization into microtubules (part of regular cell division). Also prevents activation, degranulation, and migration of neutrophils
Dosage: 1.2 mg (2 tabs) po x 1 then 0.6 mg 1 hour later
Adverse Effects: Often causes GI symptoms
• Hematologic abnormalities
• Rhabdomyolysis
• Renal dysfunction and elderly patients are at increased risk
• Concomitant use of 3A4 inhibitiors, P-gp inhibitors, fibrates, and statins may increase the risk of myopathy
• Dose adjust in renal/hepatic impairment
• CrCl < 30 ml/min
• Hepatic impairment

Question 15

Colchicine Interactions

Answer 15

Concomitant CYP 3A4 and P-gp inhibitor users
• Dose adjustments necessary
Concurrent use of colchicine and P-gp or strong CYP3A4 inhibitors is contraindicated in renal impairment &/or hepatic impairment

Question 16

Strong CYP3A4 Inhibitors - Recognize DDI with what Gout therapy?

Answer 16

DDI with Colchicine

Only including must knows:
Clarithromycin
Darunavir/ritonavir
Itraconazole
Ketoconazole

Acute Gout Flares: Single 0.6-mg dose followed by 0.3 mg 1 hour later; dose to be repeated no earlier than 3 days

Prophylaxis of Gout Flares: 0.3 mg once every other day to 0.3 mg once daily

Question 17

Moderate CYP3A4 Inhibitors - Recognize DDI with what Gout therapy?

Answer 17

DDI with Colchicine
Must knows:
Diltiazem
Erythromycin
Fluconazole
Verapamil

Acute Gout Flares: Single 1.2-mg dose; dose to be repeated no earlier than 3 days

Prophylaxis of Gout Flares: 0.3-0.6 mg daily (0.6-mg dose may be given as 0.3 mg twice daily)

Question 18

P-glycoprotein inhibitors - DDI with which Gout medication?

Answer 18

Colchicine DDI
Must know agents for exam:
Cyclosporine
Amiodarone
Ranolazine

Acute Gout Flares: Single 0.6-mg dose; dose to be repeated no earlier than 3 days

Prophylaxis of Gout Flares: 0.3 mg once every other day to 0.3 mg once daily

Question 19

Corticosteroids

Answer 19

MOA: Reduces polymorphonuclear leukocyte migration, suppresses
the lymph system
• Immune suppression and anti-inflammatory effects
Similar efficacy to NSAIDs in trials
Prednisone 30-60mg po qd for 2 days with taper over 10 days
Methylprednisolone dose pack

Question 20

MUST KNOW: Intra-articular triamcinolone doses

Answer 20

• Large joint (eg, knee): 40 mg as a single dose

• Medium joint (eg, wrist, ankle, elbow): 30 mg as a single dose

• Small joint (eg, toe, finger): 10 mg as a single dose

Question 21

Corticosteroids Use Populations

Answer 21

Consider alternative if DM, CHF or severe GERD or PUD
- Increases BG
Safe for use in renal impairment

Question 22

Chronic Therapy Agents/Goals

Answer 22

Goals of therapy: Prevent future attacks and hyperuricemic sequlae by maintaining SUA < 6.0

Xanthine - (xanthine oxidase) -> Uric Acid - (uricase) -> Allantoin

Xanthine Oxidase Inhibitors: Allopurinol, Febuxostat
Uricosurics: Probenecid
Synthetic Uricase: Pegloticase

Question 23

Allopurinol

Answer 23

Xanthine Oxidase Inhibitor
Can be used regardless of whether there is overproduction
ADRs:
Rash
• Occurs in ~2% of patients
• Potentially increased by coadministration with amoxicillin, ampicillin, thiazides, ACE-I
• Probably best to d/c the drug
• Mild rash can progress to Stevens Johnson Syndrome
Allopurinol Hypersensitivity (DRESS syndrome)
• Drug Rash with Eosinophilia and systemic symptoms
• Rash + fever + eosinophilia + hepatitis
• Occurs in 0.1% of patients
• Rate of death 20-25%
• Immediately d/c the drug

Question 24

Allopurinol DDI and Dosing

Answer 24

Warfarin - can still use but monitor INR for increased bleed risk
6-MP, azathioprine, theophylline - these meds not used often
amoxicillin, ampicillin, thiazides, ACE-I - increase risk of rash

Dosing:
Starting dose: 50-100 mg qday
• 100 mg po qd starting dose: normal renal function
• 50 mg po qd in CKD stage 4 or worse
• Increase q 2-5 weeks to target < 6 mg/dL
• May have to increase up to 800mg to achieve target SUA
• Can go above 300mg po qday even in renal impairment despite renal dosage adjustment PI recommendations - would just have to monitor more carefully

Question 25

Febuxostat (Uloric)

Answer 25

Chemically engineered, selective xanthine oxidase inhibitor • Not structurally related to allopurinol Dosing: 40 mg once daily; may increase to 80 mg once daily in patients who do not achieve a serum uric acid level <6 mg/dL after 2 weeks • No dosage adjustments required for mild-moderate renal or hepatic impairment • Severe hepatic impairment or CrCl< 30 ml/min • Not studied, caution for use If a gout flare occurs, febuxostat does not need to be discontinued (neither does allopurinol)

Question 26

Febuxostat (Uloric) ADR/CI

Answer 26

Most common ADRs: Headache, arthralgias, abdominal pain, nausea, abnormal LFTs, flushing and dizziness **BBW: Cardiovascular death: Febuxostat should only be used in patients who have an inadequate response to a maximally titrated dose of allopurinol, who are intolerant to allopurinol, or when treatment with allopurinol is not advisable** **CI: Patients concurrently receiving 6-MP, azathioprine and theophylline (same 3 as allopurinol because xanthine oxidase is involved in their metabolism)**

Question 27

Probenecid

Answer 27

MOA: Competitively inhibits the reabsorption of uric acid at the proximal convoluted tubule, thereby promoting its excretion and reducing serum uric acid levels Dosing: 250 mg twice daily for 1 week; may increase to 500 mg twice daily; if needed, may increase to a maximum of 2 g/day (increase dosage in 500 mg increments every 4 weeks). Renal dosing • **Avoid use in CrCl < 50 ml/min** • **Avoid with history of nephrolithiasis** Avoid concomitant use of probenicid and: **• Penicillin, Methotrexate, Carbapenems (Doripenem, Meropenem)** • Increased concentration due to decreased renal secretion **• Salicylates (aspirin)** • Decreased efficacy of probenecid

Question 28

Pegloticase

Answer 28

Pegylated recombinant uricase I.V. 8 mg every 2 weeks over at least 2 hours **Infusion related reactions common (Black box warning)** • Anaphylaxis and infusion reactions during and after therapy • Generally, occur within first 2 hours • Pre-med with antihistamines and corticosteroids

Question 29

Chronic Therapy - Who? When?

Answer 29

Not all patients require chronic therapy solely because elevated UA level Lifestyle modification recommended for all patients, regardless of disease activity **Chronic Therapy = UA lowering therapy + Flare prophylaxis** • UA lowering therapy initiation can illicit flares • Prophylactic flare therapy should be given concomitantly with UA lowering therapy (ULT) • **Chronic therapy should not be stopped during flare** Indications for pharmacologic treatment: **• ≥1 subcutaneous tophi, radiographic evidence of damage attributable to gout; OR frequent flares (≥2/year)** May *consider* treatment: • History of >1 attack, but <2 attacks per year • Those with first gout flare with the following characteristics • CKD stage ≥3 • [UA] > 9 mg/dL • Urolithiasis

Question 30

Gout Flare - Oral Prednisone Dose

Answer 30

0.5mg/kg for 5-10 days then stop

Question 31

See slides for treatment algorithm images, but most content is here

Answer 31

See slides