Drugs Used to Treat Gout PDF

Drugs Used to Treat Gout Pharmacology 2 (1601310) November 18,19 First Semester 2024-2025 Asst. Prof. Dr. Najlaa Saadi Sixth week: Monday,Tuesday PhD Clinical Pharmacology Gout High blood uric acid levels (hyperuricemia), causes painful joint inflammation due to urate...

Drugs Used to Treat Gout Pharmacology 2 (1601310) November 18,19 First Semester 2024-2025 Asst. Prof. Dr. Najlaa Saadi Sixth week: Monday,Tuesday PhD Clinical Pharmacology Gout High blood uric acid levels (hyperuricemia), causes painful joint inflammation due to urate crystals and can lead to kidney stones and lumpy skin deposits. Hyperuricemia Mechanisms: Excessive uric acid production Impaired renal excretion of uric acid Gout Progresses Through Four Stages: 1. Asymptomatic hyperuricemia. 2. Attacks of gouty arthritis. 3. Asymptomatic intercritical period. 4. Tophaceous gout. Aims of the Treatment of Gout: 1. Relieve acute gouty attacks 2. Prevent recurrent gouty episodes and urate lithiasis Acute Attacks  Deposition of urate crystals in the synovial space promotes inflammatory processes.  Infiltration of leukocytes inside of synovial cavity , these cells phagocytize urate crystals and then break down, causing release of destructive lysosomal enzymes  Inflammatory cells enter the joint and also release inflammatory substances, including leukotrienes ,that attract additional inflammatory cells.  Colchicine acts on microtubules in the inflammatory cells.  NSAIDs inhibit PG formation in cells of the joint. Treating Acute Gout  Indomethacin is largely replace Colchicine in the treatment of acute gouty attacks.  Colchicine relief acute gouty attacks.  Intra-articular glucocorticoids (when only one or two joints are affected. Colchicine  Colchicine relieves the pain and inflammation of gouty arthritis in 12–24 hours.  Used for the treatment of acute gouty attacks as well as chronic gout. Pharmacokinetic  Rapidly absorbed after oral administration  Metabolites are excreted in the intestinal tract and urine. Pharmacodynamics  Colchicine Binds to tubulin, inhibiting microtubule formation(the structure required for cellular motility and cell division).  Reduces leukocyte migration and phagocytosis. Indications  Terminating a gouty attack  Intercritical Prophylaxis ( at low doses) to prevents recurrent flares.  Mediterranean fever(prevent acute attacks)  Sarcoid arthritis  Hepatic cirrhosis. Adverse Effects of Colchicine  Nausea, vomiting, diarrhea and abdominal pain , result from injury to the rapidly proliferating cells of the GI epithelium.  Hepatic necrosis  Acute renal failure  Disseminated intravascular coagulation  Seizures  Hair loss (alopecia)  Bone marrow depression  Myopathy  Fetal harm( avoided during pregnancy)  Extravasation can cause local necrosis(intravenous administration of colchicine )  Acute overdose is characterized by burning throat pain, bloody diarrhea, shock, hematuria, central nervous system depression NSAIDs in Gout Inhibit prostaglandin synthesis Indomethacin is used in the initial treatment of gout as a replacement for colchicine due to colchicine’s diarrhea side effects. Aspirin is not used because it causes renal retention of uric acid at low doses (less than 2.6 g daily) All NSAIDs except aspirin, salicylates and tolmetin use to treat acute gouty episodes. Uricosuric Agents (Probenecid,Sulfinpyrazone)  Drugs that increase the excretion of uric acid.  They are decrease the body urate in patients with tophaceous gout or in those with frequent gouty attacks. Pharmacokinetics  Probenecid is completely reabsorbed by the renal tubules and is metabolized slowly with a terminal serum half-life of 5-8 hours.  Probenecid decrease secretion of weak acids& cause prolong penicillin blood levels. Pharmacodynamics  As the urinary excretion of uric acid increases, the size of the urate pool decreases  Probenecid prevents formation of new tophi and facilitate regression of tophi that have already formed. Indications  Uricosuric therapy should be initiated in gouty patients with under excretion of uric acid when allopurinol or febuxostat is contraindicated or when tophi are present.  The drug may exacerbate acute episodes of gout, therefore treatment should be delayed until the attack has been controlled. Adverse Effects of uricosuric Agents (Probenecid,Sulfinpyrazone) 1. GI irritation 2. Hypersensitivity reactions (rash) 3. Nephrotic syndrome : patients should consume 2.5-3 liters of fluid daily during initial treatment and maintain a urine pH above 6.0 using alkali to prevent stone formation 4. Aplastic anemia (rarely) Xanthine Oxidase Inhibiter Allopurinol Pharmacokinetics  Allopurinol is metabolized by xanthine oxidase, but the resulting compound, alloxanthine, retains the capacity to inhibit xanthine oxidase and has a long enough duration of action so that allopurinol is given only once a day. Pharmacodynamics  Allopurinol and its active metabolite- alloxanthine- reduce uric acid production, by inhibition of xanthine oxidase, an enzyme required for uric acid formation from breakdown of DNA Indications  Allopurinol is often the first-line agent for the treatment of chronic gout in the period between attacks and it aims to prolong the intercritical period.  Treats primary hyperuricemia in gout and secondary hyperuricemia associated with conditions like malignancies or renal disease  This agent is the drug of choice in those with a history of kidney stones.  When initiating allopurinol, colchicine or NSAID should be used until steady-state serum uric acid is normalized or decreased to less than 6 mg/dL and they should be continued for 3-6 months. Adverse Effects 1. Nausea, vomiting, diarrhea 2. Peripheral neuritis 3. Necrotizing vasculitis 4. Bone marrow suppression 5. Hepatic toxicity 6. Interstitial nephritis 7. Allergic skin reaction 8. Cataracts (Allopurinol binds to the lens) Interactions & Cautions  When chemotherapeutic purines (eg, azathioprine) are given concomitantly with allopurinol, their dosage must be reduced by about 75%.  Allopurinol inhibits the metabolism of probenecid and oral anticoagulants.  Safety in children and during pregnancy has not been established. Pegloticase Ricombinant uricase enzyme that converts uric acid into a more soluble compound that is easier to excrete Severe treatment-resistant forms of gout (don't respond to multiple other forms of therapy including NSAIDs, allopurinol, colchicine & steroids