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Pharm exam 2 > Gout > Flashcards

Gout Flashcards

1
Q

Hyperuricemia

A
  • Elevated serum uric acid levels.

- Seen in renal disease, CV disease, and metabolic disease.

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2
Q

Gout

A

Characterized by acute attacks of join inflammation, resulting from deposition of urate crystals in the joint or other tissues.

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3
Q

Pathogenesis of gout

A
  • Crystallization of urate in the synovial fluid & joint tissue
  • Crystal-induced inflammatory response
  • PMNs phagocytize crystals
  • Release of kinins & lysosomal enzymes
  • Tophi-uric acid crystals deposits.
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4
Q

Epidemiology of hyperuricemia

A
  • Serum rate level of >7 in men, >5.7 in woman
  • prevalence increases with age
  • primarily effects men 3:1
  • estrogen promotes uric acid renal excretion.
  • Age >40, alcohol intake, renal insufficiency
  • Drug therapy for HTN, CHF, renal insufficiency (diuretics, low dose ASA)
  • metabolic syndroms (obesity, HL, HTN, hyperglycemia)
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5
Q

Gout enzyme defects

A
  • HGPRT-ase deficiency

- Increased PRPP synthetase activity

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6
Q

Diagnosis of gout

A
  • Joint aspirate-irate crystals in joint fluid
  • Biopsied tophus contains urate cyrstals
  • clinical diagnosis, based on criteria.
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7
Q

Gout clinical presentation

A
  • Go to bed feeling well
  • Awakened by severe pain in great toe
  • Pain rapidly becomes more severe
  • Cannot tolerate touch
  • Often unable to sleep or carry out activities of daily living due to pain
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8
Q

Clinical diagnosis (6 of 12)

A
  • Unilateral attack involving the tarsal
  • Suspected tophus
  • Hyperuricemia
  • Asymmetric swelling within joint on x-ray
  • Subcortical cysts without erosions on x-ray
  • Negative culture of joint fluid
  • More than 1 attack of acute arthritis
  • Maximal inflammation within 1 day
  • Monoarticular
  • Joint redness
  • 1st metatarsophalangeal joint painful or swollen
  • Unilateral attack involving 1st metatarsophalangeal joint
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9
Q

Is hyperuricemia always present with gout?

A

No, serum uric acid may fall during an acute gouty attack.

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10
Q

Elimination of uric acid

A
  • Extrarenal-GI tract. -About 100mg/day eliminated via GI tract through secretions
  • Uric acid degraded by bacteria
  • GI excretion can greatly increase in renal failure
  • Glomerular filtration- 95%
  • Early proximal tubular reabsorption- 98%
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11
Q

Probenecid

A

-prevents uric acid from reabsorption

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12
Q

Lesinurad

A

-A selective uric acid reabsorption inhibitor the acts through the URAT1 transporter, which is responsible for most reabsorption of filtered uric acid from the renal tubular lumen.

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13
Q

Allopurinol and Febuxostat both block _____

A

xanthine oxidase

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14
Q

Being deficient in HGPRT- ase leads to…..

A

higher amounts of uric acid.

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15
Q

Pathogenesis of hyperuricemia

A
  • Increased production (high cell burden tumors)

- Decreased elimination of uric acid: renal disease, diuretics, low doses of ASA, alcohol, cyclosporine

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16
Q

Treatment of hyperuricemia

A
  • Usually not treated.

- 70% of patients have correctable underlying cause

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17
Q

What are underlying causes of hyperuricemia

A
  • Drugs
  • Alcohol intake
  • Obesity
  • Renal insufficiency
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18
Q

Acute gout attack management

A
  • NSAIDs, corticosteroids, colchicine
  • May be appropriate to use more than 1 agent
  • ICE for inflammation
  • Opioids for severe pain
  • Colchicine may be more toxic than NSAIDs and corticosteroids
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19
Q

NSAID tx of acute gout attack

A
  • Intermittent therapy- continue at full dose until attack has resolved
  • Indomethacin
  • Naproxen
  • Sulindac
  • Ketorolac
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20
Q

Corticosteroids

A
  • Good for elderly, resistant cases to NSAIDs & colchicine, or transplant pts
  • Prednisone
  • Intra-articular corticosteroids & lidocaine
  • Triamcinolone acetone
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21
Q

Prednisone dose

A

20-50 mg/day until relief

high doses for 2-5 days, then taper for 7-10 days, or high dose for 5-10 days, then stop.

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22
Q

administration of intra-articular corticosteroids & lidocaine

A
  • Systemic therapy contraindicated

- With joint aspiration.

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23
Q

Triamcinolone acetonide dose

A

60 mg IM + po prednisone.

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24
Q

MOA of colchicine

A
  • Anti-inflammatory agent
  • Inhibition of monosodium urate-induced NALP3 inflammasome activity in macrophages
  • alteration in adhesion molecule expression on expression on endothelial cells and neutrophils, thus reducing neutrophil adhesion and recruitment into inflamed joints
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25
Q

How is colchicine excreted

A

30% of drug cleared through kidney.

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26
Q

What is colchicine contraindicated with

A
  • Contraindicated with P-gp inhibitors-DDIs

- P-gp is thought to limit colchicine GI absorption, thus P-gp inhibitors may lead to accumulation of colchicine

27
Q

How is colchicine metabolized?

A

via CYP450 3A4

28
Q

colchicine high dose regimen

A

High dose: 0.6-1.2mg initially, then 0.6mg every hour until

  • Pain relief
  • Diarrhea or other GI symptoms
  • Cumulative dose of 4.8mg
29
Q

colchicine low dose regimen

A

Low dose regimen: 1.2mg initially, followed by 0.6mg 1 hr later (total dose is 1.8mg) – then can be followed 12 hours later by 0.6 mg daily-bid, until gout attack resolves
-low dose regimen is preferred due to toxicity with high dose

30
Q

time window to begin colchicine treatment

A

36 hr of attack onset- not effective if start later

-should see pain relief by 48 hr.

31
Q

Colchicine adverse effects

A

-GI effects (N/V/D)
-Hepatotoxicity
-Nephrotoxicity
-Neurotoxicity
Myopathy (check CK q6mon with CrCl ,50)
-Bone marrow depression
-Alopecia

32
Q

Maintenance therapy for chronic gout

A

-Decrease serum uric acid levels (<6 or <5)

33
Q

Maintenance diet

A
  • Avoid/decrease high purine foods
  • Avoid/decrease alcohol intake
  • Avoid high fructose-sweetened drinks
  • Limit carbs
  • Vit. C
  • Weight reduction
  • Adequate fluid intake e
34
Q

Maintenance therapy

A
  • Allopurinol & Febuxostat
  • Uricosurics
  • Prophylaxis of NSAIDs, Colchicine, prednisone
35
Q

Colchicine disadvantages

A
  • No decrease in serum uric acid levels
  • Does not prevent tophi formation
  • Adverse effects
36
Q

Colchicine advantage

A

-Prevents gouty attacks during initiation of xanthine oxidase inhibitors or uricosurics

37
Q

colchicine prophylaxis dosing

A
  • 0.6 mg daily or BID

- Lower dosing with CrCl <50

38
Q

2 xanthine oxidase inhibitors

A
  • Allopurinol (inexpensive)
  • Febuxostat
  • No comparison of which is more effective
39
Q

Xanthine oxidase inhibitors are excellent choices for

A
  • Renal impairment
  • Tophi
  • Renal stones
  • Induction chemotherapy
40
Q

Xanthine oxidase inhibitors MOA

A
  • Decrease serum uric acid levels
  • Increase in hypoxanthine and xanthine levels
  • Increased renal excretion of hypoxanthine and xanthine
  • Reduces crystalluria
  • no anti-inflammatory effect
  • No uricosuric effect
41
Q

MOA of Allopurinol/Febuxostat

A
  • Allopurinol converted to oxipurinol by xanthine oxidase. Oxipurinal has longer half life and responsible for most of activity.
  • Inhibits hypoxanthine to xanthine
  • Increase amount that is excreted as hypoxanthine and xanthine but decreasing amount that is excreted as uric acid.
  • Both drugs block xanthine oxidase.
42
Q

Allopurinol pharmokinetics

A
  • Oxypurinol is the active metabolite of allopurinol
  • T1/2 of allopurinol is 2-3hr
  • T1/2 of oxypurinol is 18-30 hr
  • Oxypurinol is extensively reabsorbed in kidney
  • Long t1/2 permits once daily dosing
43
Q

Dosage of allopurinol

A
  • initiate with small doses-100mg/day
  • Use prophylactic colchicine or NSAIDs
  • increase by 100mg/day every week
  • Final dose: 200-300 mg/d up to 400-600 mg/d
  • Adjusted to serum uric acid concentration
  • special testing for Han Chinese and Thai
44
Q

Allopurinol onset of action

A
  • Serum uric acid levels fall in 1-2 days
  • Maximal suppression of serum uric acid in 7-10 days
  • Clinical improvement in approximately 6 months
  • Therapy should be continued indefinitely
45
Q

Allopurinol adverse effects

A

-Hematological-rare
-Rashes
-Stevens-Johnson syndrome/TEN
-Hypersensitivity reactions
-Hepatotoxicity
GI-N/V/D
-Long-term increased risk of cataracts

46
Q

Febuxostat-Uloric

A
  • More potent inhibitor of xanthine oxidase than allopurinol
  • Inhibits both the oxidized and reduce forms of xanthine oxidase
47
Q

Febuxostat dosing

A
  • Initiate 40mg/day, increase to 80mg/day at 2 weeks, if uric acid level is not within target range
  • do not need lower doses for renal or hepatic dysfunction
48
Q

Febuxostat pharmokinetics

A
  • 99% protein bound, active metabolites

- Weak inhibitor of CYP2D6

49
Q

Febuxostat Adverse Effects

A
  • Fewer problematic ADRs than allopurinol
  • LFT elevation 5-6%
  • Arthralgias
  • Rash
  • Nausea
  • Most use after allopurinol
50
Q

Probenecid

A
  • Can be added on to XOI

- Management of underexcretors of uric acid

51
Q

Probenecid MOA

A

Inhibits proximal tubule reabsorption of uric acid

52
Q

Probenecid dietary clearance

A
  • Normal <800mg/day
  • Borderline overproducer 800-1000mg/day
  • definite overproducer >1000 mg/day
53
Q

Probenecid contraindications

A
  • Only used with pt’s with CrCl >50 who are clearly underproduces of uric acid
  • no hx of urolithiasis
54
Q

Probenecid dosing

A
  • Probenecid 250mg BID x2wks, then 500 mg BID
  • total dose 1-1.5gm/day
  • Decrease maintenance dose after serum uric acid lowered
  • Maximal renal excretion 30-60 min after dose
  • Pt should increase fluid intake
55
Q

Disadvantages of probenecid

A

-Should not be used in renal impairment
-Renal stone formation due to uricosuria
-Uricosuric effect antagonized by ASA
-Exacerbate gout attacks in early therapy
-No anti-inflammatory effect
DDis-organic transport in kidneys

56
Q

Probenecid adverse effects

A
  • Headache
  • Hypersensitivity reactions
  • GI effects
  • Renal stone formation – increase fluid intake
  • Rare
  • Nephrotic syndrome
  • Hepatic necrosis
  • Blood dyscrasias
57
Q

Lesinurad-Zurampic

A

URAT1 inhibitor of uric acid reabsorption

  • Used in combination with XOI if target serum uric acid level not reached with XOI alone
  • higher frequency of renal ARDs if lesinurad used alone
  • studied show effectiveness with allopurinol and Lesinurad, not as much with febuxostat
58
Q

Lesinurad Dosing

A

-200 mg daily if CrCl >45-60ml/min

59
Q

Lesinurad PK

A 
T1/2= 5 hours 
Bound to plasma proteins
Metabolized via CYP2C9
30% excreted unchanged in urine 
Weak inducer of CYP3A4
60
Q

Pegloticase

A

used with very resistant attacks
Very expensive drug
Recombinant enzyme
Not very effective
Antibody formation may decrease effectiveness and increase risk of infusion reactions
Appropriate for pt’s with severe gout disease burden and refractoriness or intolerance to ULT

61
Q

Pegloticase dosing

A

8mg IV over no less than 2 hours every 2 weeks until reach target uric acid level
hold dose if uric acid <6
-premedicate with antihistamines and corticosteroids
-Start NSAID, corticosteroid or colchicine prophylaxis 1 week before 1st infusion

62
Q

Refractory Gout management

A
  • Attempt upward dose titration of 1 XOI to max dose.

- Addition of uricosuric agent to an XOI drug

63
Q

Rilonacept-Arcolyst

A
  • Not approved for gout, but used as urate lowering therapy
  • Inhibits IL-1 as a decoy receptor that binds IL-1 beta, preventing its interaction with cell surface receptors. It also binds IL-1 with reduced affinity
  • SQ dosing

Pharm exam 2 (6 decks)

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