Gout Pharmacotherapies Joseph Kitzmiller MD PhD FCP 5086 Graves Hall Assistant Professor – Biological Chemistry & Pharmacology

Suggested/Optional Readings (see Resources tab for pdfs of the following suggested/optional readings) Gout Pharmacology: Katzung Chapter 36 Pages Corticosteroids: Katzung Chapter 39 Pages 2-11

Learning Objectives For the bone-homeostasis pharmacotherapies presented in this module, describe the following:  primary mechanisms of action  indications/uses  common toxicities  cross-reactions with other medications

Gout Drugs  Several medications are used to treat patients with gout. Some are used to treat acute gout and some are used to manage patients with chronic gout, preventing future gout and minimizing long-term complications of gout (joint destructions and renal damage)  GOUT: hyperuricemia → uric acid crystals In joints: uric acid crystals → pain, swelling, stiffness, deformity, and impaired movement In kidneys: uric acid crystals → renal damage & scarring, and potentially renal insufficiency and ultimately renal failure

Gout Drugs  ACUTE GOUT DRUGS  Nonsteroidal anti-inflammatory drugs (NSAIDs)  Colchicine  Corticosteroids  CHRONIC GOUT DRUGS  Uricosuric agents  Xanthine oxidase inhibitors  Colchicine*

Nonsteroidal anti-inflammatory drugs (NSAIDs) Protypical member: Ibuprofen Indication: 1 st line for acute gout Mechanism of Action: Inhibit prostaglandin synthesis & inhibit urate crystal formation Non-selective reversible inhibition of COX1 and COX2 Adverse Effects: Gastric erosions & bleeding (due to ↓ PGE2 and ↓ prostaglandin synthesis) Renal Insufficiency (due to ↓ prostaglandin synthesis) Hypersensitivity reaction (urticaria) Other NSAIDs include ketoprofen, indomethacin, ketorolac, naproxen, and meloxicam, acetaminophen Aspirin Do not use aspirin for gout → renal retention of uric acid

Corticosteroids Protypical members: SHORTER-ACTING Prednisone & Cortisone (PO); Hydrocortisol (PO, top, inj); Prednisolone & Methylprednisolone (PO, inj) LONGER-ACTING Triamcinolone, Betamethasone and Dexamethasone (PO, inj, top) Indication: Used occasionally for severe symptomatic gout Mechanism of Action: Intracellular regulation of genes → Anti-inflammation (↓ production of prostaglandins & inflammatory cells (T & B cells, macros, baso & eosinophils) Adverse Effects: Widespread Intracellular regulation of genes → catabolic/anti-anabolic effects → immunosuppressive effects → adrenal insufficiency NOTE: Long term use of corticosteroids can lead to osteoporosis.

Colchicine Indication: Used for acute gout & for patients with chronic gout taking allopurinol Route: PO or IV Mechanism of Action: Binds intracellular tubulin→polymerizes microtubules→inhibits leukocyte migration & phagocytosis also inhibits formation of leukocyte B4 Adverse Effects: diarrhea, nausea & vomiting, abdominal pain, hepatic necrosis, acute renal failure, DIC, seizures, peripheral neuritis, myopathy Long-term use Adverse Effects: Bone marrow suppression agranulocytosis and suppression of hair follicle growth (alopecia)

Uricosuric Agents Protypical members: Probenecid & Sulfinpyrazone Indication: Used for patients with chronic gout Mechanism of Action: Inhibits uric acid reabsorption in kidneys → accelerated excretion of urate Adverse Effects: Formation of uric acid renal stones GI irritation Inhibits renal excretion of penicillins, indomethacin & sulfonylureas

Xanthine oxidase inhibitors Protypical member: Allopurinol (purine) Febuxostat (non-purine) Rasburicase & Pegloticase (recombinant of urate oxidase) Indication: Chronic gout: allopurinol is standard-of-care between episodes of gout Mechanism of Action: Inhibit production of uric acid by inhibiting xanthine oxidase Adverse Effects: Allergic skin reaction. Allopurinol by itself can precipitate acute gouty arthritis so typically given along with colchicine*. Important Drug Interactions: Mercaptopurine, azathioprine & theophylline doses typically need ↓75%

SUMMARY: Gout Drugs  ACUTE GOUT DRUGS  Nonsteroidal anti-inflammatory drugs (NSAIDs)  Colchicine  Corticosteroids  CHRONIC GOUT DRUGS  Uricosuric agents  Xanthine oxidase inhibitors  Colchicine*