02-27 Gout PHARM

Question 1

EXPLAIN the two main reasons for working either to treat an acute attack of gouty arthritis, OR to lower a chronically elevated serum uric acid level

Answer 1

.

Question 2

REVIEW the chemistry of, and biochemistry of, uric acid

Answer 2

product of pruine metabolism

Question 3

DESCRIBE the problems that uric acid can cause when it accumulates to excess at various sites and tissues

Answer 3

arthritis in joint

tophi in bursae

kidney stones

Question 4

Basic Pharm Card: naproxen for gout

• Class
• Action
• Kinetics
• ADRs
• Interactions

Answer 4

• Class: FIRST LINE FOR ACUTE ATTACK NSAID (non-selective), anti-inflammatory, analgesic, antipyretic
• Action: inhibit COX 1 and 2, reducing production of inflammatory prostaglandins. Helps to relieve severe pain from gout within hours to days
• Kinetics: Well absorbed when taken orally (95%); renally excreted (95%); can be taken twice per day
• ADRs: gastric upset, gastritis, ulceration, ARF; avoid in patients with “allergy” to aspirin; fluid retention and edema
• Interactions: reduce activity of antihypertensives; may increase risk of GI bleeding with warfarin

Question 5

Basic Pharm Card: colchicine for gout

• Class
• Action
• Kinetics
• ADRs
• Interactions

Answer 5

Class: SECOND-LINE FOR ACUTE ATTACK antigout drug for both acute attacks and for prevention

Action: not entirely clear; seems to reduce leukocyte migration, reduce phagocytosis, reduce inflammatory response induced by uric acid crystals

Kinetics: Well absorbed when taken orally; distributes rapidly to tissues, concentrated in leukocytes; metabolized partially in liver, then excreted in bile; half-life 10-20 h

ADRs: most commonly nausea, vomiting, diarrhea–these are usually dose-limiting

Interactions: erythromycin and other macrolides may increase risk of toxicity

Dose: prevention: 0.5 mg daily; treatment of acute gout: 1 mg po, then 0.5 mg po q1-2 h prn pain; keep total daily dose <4 to 8 mg; give until pain relieved or develop N/V, diarrhea

Question 6

Basic Pharm Card: prednisone for gout

• What #choice?

Answer 6

3rd line choice for acute attack

Question 7

REVIEW the basic pharmacology of allopurinol for the long-term management of elevated levels of uric acid

• Class
• Action
• Kinetics
• ADRs
• Interactions

Answer 7

Class: antigout drug, xanthine oxidase inhibitor

Action: by blocking the enzyme xanthine oxidase (with its own metabolite), leads to less uric acid produced, and more hypoxanthine and xanthine in both blood and urine; when begun, may need to give colchicine as well to prevent acute flare of gout

Kinetics: Well absorbed PO; metabolized quickly to oxypurinol, t1/2 ~15 h; about 70% excreted in urine as oxypurinol

ADRs: hypersensitivity vasculitis, agranulocytosis, hepatic necrosis, TEN/Stevens Johnson syndrome; can precipitate an acute attack of gout

Interactions: dramatic increase in toxicity of azathioprine and 6-MP; doses need to be reduced

Question 8

REVIEW the basic pharmacology of probenecid for the long-term management of elevated levels of uric acid

• Class
• Action
• Kinetics
• ADRs
• Interactions

Answer 8

Class: sulfonamide derivative, uricosuric agent, adjunct to Penicillin G treatment

Action: competitively inhibits the active reabsorption of uric acid at the PCT,thereby increasing urinary excretion of uric acid (uricosuric effect); also competitively inhibits the active tubular secretion of Pen and other weak acid antibiotics, thereby leading to higher serum levels

Kinetics: Well absorbed when taken orally; cleared by both liver metabolism and urinary excretion; usually given bid; half-life 4-17 h

ADRs: contraindicated with previous allergy, or those with uric acid kidney stones; risk of aplastic anemia, hepatic necrosis, allergy; can precipitate an acute attack of gout!!

Interactions: may significantly slow the renal clearance of drugs such as Pen G, cephalosporins, MTX (methotrexate)

Question 9

REVIEW the basic pharmacology of pegloticase for the long-term management of elevated levels of uric acid

• Class
• Action
• Kinetics
• ADRs
• Warnings

Answer 9

Class: A pegylated urate oxidase enzyme (recombinant mammalian enzyme, produced in E. coli) approved by FDA for IV treatment of chronic severe symptomatic gout in adults who have not responded to, or can’t tolerate, older and simpler treatments (and less expensive!)

Action: Uricase catalyzes oxidation of uric acid to allantoin, a metabolite that is inert, water soluble, and cleared by the kidney; a single injection produces maximal reduction in serum urate within 24 hours; For the endpoint of producing uric acid levels <6 mg/dL >80% of the time, success rates were 38-47% ( 8 mg q2weeks), 20-49% (8 mg q4weeks), 0% (placebo)

Kinetics: As an active enzyme, must be given IV; generally maintains serum uric acid <6 mg/dL for up to 12 days; must be given q2weeks

ADRs: antibodies develop in 92% of patients; make drug less effective; occasionally (4/85 patients) can cause anaphylaxis; can precipitate acute attacks of gout; should receive an antihistamine and a corticosteroid prior to infusion; prophylaxis with an NSAID or colchicine recommended for 6 months

Warnings: should be given in a healthcare setting by providers capable of managing anaphylaxis•Dose: 8 mg IV every 2 weeks; see next slide for other costs•

Question 10

•A 45-year-old man was found to have mild essential hypertension, and was begun on hydrochlorothiazide 25 mg po qd as monotherapy. This successfully lowered his blood pressure over the next 4 weeks. However, one month after starting this medication, he developed an acutely red, hot, and intensely painful first metatarsal-phalangeal joint. Joint aspiration revealed some white blood cells, no organisms, and some yellow, needle-shaped negatively birefringent crystals. His serum uric acid was 9.5 mg/dL (normal <6.8 mg/dL). The most commonly used first line treatment (because of favorable benefit-to-risk ratio) to reduce his pain and inflammation as quickly as possible would be to:

• A. Increase hydrochlorothiazide to 50 mg daily
• B. Begin naproxen sodium 440 mg orally twice per day
• C. Begin allopurinol 300 mg orally once per day
• D. Begin probenecid 500 mg orally twice per day
• E. Begin prednisone 60 mg intra-articularly once per day

Answer 10

B, I think…