NR566 Week $ Study Guide_Chapter 25: Drugs Used in Treating Inflammatory Processes

NR 566 Week 4 Study Guide Chapter 25: Drugs Used in Treating Inflammatory Processes Gout medications Drugs: Anti-gout agents: allopurinol (Zyloprim), colchicine, and febuxostat (Uloric) Uricosuric agents: probenecid (Benemid) and sulfinpyrazone (Anturane) o Peak incidence 70 to 79 years old, more common in men than women o Gout in women occurs exclusively post-menopausal and is associated with HTN, renal insufficiency, and diuretics o Gout Syndrome: Caused by an alteration in purine metabolism: end product is uric acid o Hyperuricemia and deposition of urate crystals in various tissues o Four phases: asymptomatic hyperuricemia, acute gouty arthritis, inter-critical gout, and chronic tophaceous gout o Those with asymptomatic hyperuricemia do not require treatment (diet and lifestyle changes) o Acute gout is characterized by sudden onset of pain, erythema, limited ROM, and swelling of the involved joint  50% of cases involve the first metatarsal joint of the great toe o Key elements in Tx include management of the acute pain and use of antigout and uricosuric agents o Pain: NSAIDS and corticosteroids Pharmacodynamics Antigout Drugs (allopurinol, colchicine, and febuxostat) o Act to reduce the inflammatory process or to prevent the synthesis of uric acid o Allopurinol and febuxostat inhibit xanthine oxidase: enzyme responsible for conversion of hypoxanthine and xanthine to uric acid o Allopurinol has a metabolite (alloxanthine): also an inhibitor of xanthine oxidase o Allopurinol acts directly on purine metabolism, reducing the production of uric acid, without disrupting biosynthesis of vital purines o Allopurinol and febuxostat are the only drugs that act directly on the pathophysiological cause of gout o Allopurinol decreases both serum and urinary uric acid in 2 to 3 days: dose dependent  A week or more of Tx may be necessary before the full effects can be seen o Febuxostat is used to treat hyperuricemia in patients with gout o Goal is to have uric acid level of less than 6 mg/dL o Can take 2 weeks or more to see the effects of febuxostat o Colchicine: does not affect purine metabolism o Binds to the microtubular proteins to interfere with the function of the mitotic spindles and inhibit migration of granulocytes to the inflamed area o Reduces lactic acid production by granulocytes: decreases deposition of uric acid o Interferes with kinin formation and reduces phagocytosis o Taken together: these actions decrease the inflammatory response to the deposited urate crystals o Relives pain in acute attack: not an analgesic o Its prophylactic, suppressive effect helps reduce the incidence of acute attack and relives patient’s occasional residual pain and mild discomfort Uricosuric drugs: probenecid (Benemid) and sulfinpyrazone (Anturane o These drugs increase the rate of uric acid secretion in the urine o Both drugs inhibit renal tubular reabsorption of urate and thus increase the renal excretion of uric acid and decrease serum uric acid levels. o Effective uricosuria reduces the miscible urate pool, retards urate deposition, and promotes reabsorption of urate deposits o Sulfinpyrazone competitively inhibits platelet prostaglandin synthesis: prevents platelet aggregation (antithrombotic effects) o Both drugs lack anti-inflammatory activity o Most useful in patients with reduced urinary excretion of uric acid o Not intended for Tx of acute attacks Pharmacotherapeutics o Allopurinol (Zyloprim) colchicine, probenecid (Benemid, and sulfinpyrazone (Anturane): poor urate clearance in the presence of renal impairment o Use with caution: renal function tests performed regularly to determine dosage o Data is insufficient regarding febuxostat in renal impairment o Allopurinol and colchicine: hepatotoxicity o Not recommended for patients with severe hepatic dysfunction o If anorexia, weight loss, or pruritus, evaluate LFTs o For milder hepatic disorders: close monitoring of LFTs is required o Colchicine, probenecid, and sulfinpyrazone: used cautiously in PUD or spastic colon o GI ADRs from these drugs are likely to make these disorders worse o Sulfa allergy: do not use probenecid and sulfinpyrazone: sulfa-based drugs o Febuxostat, a xanthine oxidase inhibitor, is contraindicated in patients being treated with drugs requiring xanthine oxidase for metabolism: o Azathioprine, mercaptopurine, or theophylline o Risk for toxicity o When febuxostat is started there is a risk of a gout flare up: concurrently treat with NSAID or colchicine for up to 6 months o Allopurinol Preg Cat C: no adequate data o Colchicine Category C PO and D when IV/IM o Can cause fetal harm when administered to pregnant women o Probenecid is Preg cat B o Sulfinpyrazone: cat D: not much data for pregnant women o Avoided in Pregnancy o Febuxostat Cat C: no adequate studies in pregnant women o These drugs are not indicated for use in children except in hyperuricemia associated with Tx of malignancy (specialist care) o Probenecid: retarding PCN or cephalosporin excretion in selected infections ADRs o GI ADRs: colchicine, probenecid, and sulfinpyrazone o NVD, and ABD pain o Particularly troublesome for patients with Hx of PUD or active PUD o Hypersensitive reactions with sulfa allergy: probenecid and sulfinpyrazone o Severe, anaphylactic reactions are rare and typically occur within several hours after first dose, following prior use of the drug o Allopurinol: maculopapular skin rash, sometimes scaly or exfoliative o Incidence increased with renal disorders o Skin reactions may be severe and sometimes fatal: d/c at first sign of rash o The most severe reactions include: fever, chills, arthralgia, cholestatic jaundice, eosinophilia, mild leukocytosis, or leukopenia o Patients on standard therapy with colchicine who have elevated plasma levels r/t renal function have developed myopathy and neuropathy that resulted in weakness o Often unrecognized and misdiagnosed as polymyositis or uremic neuropathy o Proximal weakness and elevated creatinine kinase are generally present o Resolves in 3 to 4 weeks was drug withdrawal o Colchicine: induces reversible malabsorption of B12 o Febuxostat: risk of liver function abnormalities (40 mg/day) and nausea an arthralgia at 40 mg/day Drug Interactions o Colchicine: very few drug interactions o Probenecid, allopurinol, and sulfinpyrazone: many drug interactions o Always check the drug regimen before starting these drugs Drug of choice for treatment of gout and most common adverse effects • The main adverse reaction for all these drugs is GI distress. • Taking these drugs with food or milk may minimize gastric irritation. • Probenecid and sulfinpyrazone are sulfa-based drugs that have been associated with hypersensitivity reactions related to this base. Patients should be asked about sulfa allergies and taught the indications of a hypersensitivity reaction and the importance of reporting it. A hypersensitivity reaction requires immediate discontinuance of the drug. Other symptoms to report with these drugs include sore throat, fatigue, yellowing of the skin or eyes, and unusual bleeding or bruising. These drugs have been associated with blood dyscrasias and hepatotoxicity. • Allopurinol is the drug of choice because it is the only drug in this group that blocks urate production. • Drowsiness and dizziness have occasionally affected patients who are taking allopurinol • Allopurinol or febuxostat is best for patients who overproduce uric acid • Probenecid is best for pt who under secrete uric acid ( good renal function) • Sulfinpyrazone is best for pt who under secrete and need antiplatelet Role of NSAID use in treatment of gout: indomethacin, naproxen, sulindac and ibuprofen and ketoprofen. Used to treat inflammation. Gout medications that require renal or hepatic dose adjustments • Colchicine: renal and hepatic • Allopurinol: renal and hepatic • Febuxostat: liver function test at 2 and 4 months Allopurinol drug interactions and medications to avoid • ACEs: avoid concurrent use • Aluminum salts: separate administration • Ampicillin: risk for rash, warm patients • Anticoagulants: use warfarin for anticoagulation • Cyclophosphamide (if used monitor bleeding) • Theophylline: decreased theophylline clearance, risk for toxicity: select different respiratory drug • Thiazide diuretics (avoid concurrent use) • Thiopurines ( avoid concurrent use ) • Uricosuric agents (dosage adjustments). Signs of aspirin toxicity Toxicity: • The acute lethal dose of salicylates in adults is 10-30 g, and in children it is 3 g. • Chronic salicylate toxicity can occur when more than 100mg/kg is ingested daily for 2 or more days. • Signs of salicylate poisoning appear at serum levels of 30-60mg/dL. • Respiratory alkalosis is seen initially. • Hypernea and tachypnea occur as a results of increased CO2 production and a direct stimulatory effect of the salicylate on the respiratory center in the brain. • Other symptoms include nausea, vomiting, hypokalemia, tinnitus, disorientation, irritability, seizures, dehydration, hyperthermia, thrombocytopenia, and other hematological disorders. Treatment of Toxicity: • Induction of emesis or gastric lavage to remove any unabsorbed drug from the stomach. • Activated charcoal diminishes salicylate absorption if it is given within 2 hours of ingestion. • Salicylate levels, acid-base, fluid, and electrolyte balances are carefully monitored. • The rest of therapy is supportive • Forced alkaline diuresis by administering sodium bicarbonate increases salicylate excretion. • Hemodialysis for severe poisoning.