Pharmacological Management of Gout PDF

MSKS: Pharmacology PHARMACOLOGY MANAGEMENT OF GOUT Launa M. J. Lynch, Ph.D. Associate Professor of Pharmacology Office: 362 | Phone: 208.795.4376 [email protected] “With confidence, you have won before you have started.” - Marcus Garvey 1 Learning Objective...

MSKS: Pharmacology PHARMACOLOGY MANAGEMENT OF GOUT Launa M. J. Lynch, Ph.D. Associate Professor of Pharmacology Office: 362 | Phone: 208.795.4376 [email protected] “With confidence, you have won before you have started.” - Marcus Garvey 1 Learning Objectives š Describe the mechanism of action and adverse side effects of the drugs used to treat gout. š Compare and contrast the acute gout and chronic gout treatment 2 Textbook and Reading Assignment š READING ASSIGNMENTS š Chapter #49, Integrative Inflammation Pharmacology: Gout. In Golan, DA, Armstrong EJ, Armstrong AW. Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy, 4e, Philadelphia, PA: Wolters Kluwer/Lippincott Williams & Wilkins. š Chapter #49 Golan 3  Gout š A uniquely human disease due to the lack of Uricase is the enzyme uricase not found š Uricase metabolizes purine breakdown in humans products to the water-soluble substance allantoin š Humans excrete most purines as the sparingly soluble uric acid š High plasma levels of uric acid can lead to deposition of uric acid crystals in peripheral joints and urate is less soluble at lower temperatures, which may explain the peripheral distribution of urate crystal deposition. 4 Purine Synthesis š 2 pathways: De novo and salvage š De novo Synthesis: š The reaction between PPRP and glutamine is catalyzed by the enzyme amindoPRT š AmindoPTR is allosterically active by high levels of PPRP š Yes, PPRP is both a substrate and activator or amindoPRT š High levels of PPRP increase de novo purine synthesis PRPP = phosphoribosyl pyrophosphate amindoPRT = amido phosphoribosyltransferase HGPRT = hypoxanthine-guanine phosphoribosyltransferase Golan Figure 49-1 5 Purine Synthesis š 2 pathways: De novo and salvage š Salvage Pathway: š HGPRT phosphorylates and ribosylates dietary adenine and guanine, forming the purine nucleotide, ATP, and GTP Golan Figure 49-1 6 Purine Metabolism š Degradation occurs through a convergent mechanism š Degradation converts purines and purine nucleotides into hypoxanthine, and xanthine oxidase converts hypoxanthine to xanthine and ultimately to uric acid š Uric acid is excreted by the kidneys or gastrointestinal tract š A high de novo synthesis pathway activity increases purine degradation and results in higher plasma uric acid concentrations š In contrast, increased salvage pathway activity results in decreased de novo synthesis and decreased plasma uric acid concentrations Golan Figure 49-1 7  Pathophysiology of Gout š 99% of uric acid is in the ionized, urate form š Normal human plasma levels of urate are 4-6 mg/dL š Plasma becomes saturated at urate levels exceeding 6.8 mg/dL 8  Genetics of Gout š Issues with HGPRT š Lesch-Nyhan syndrome š Inherited absence of HGPRT š Characterized by self-mutilation, intellectual disability, and hyperuricemia š Polymorphisms in HGPRT gene that lead to decreased HGPRT synthesis or activity are thought to explain some cases of hereditary gout 9  Genetics of Gout š 65% by kidney š ~90% of uric acid is reabsorbed by the urate transport 1 (URAT1) expressed in the kidney proximal tubule š Kidney failure often leads to high plasma urate levels š 35% by GI tract š Issues with URAT1 š Urate transport 1 (URAT1) is expressed in the kidney proximal tubule š URAT is the major mediator of uric acid reabsorption š Uric acid is eliminated by the kidney by 65% š Polymorphisms in URAT1 may predispose a patient to the development of gout 10 Gout š Non-pharmacological therapies š Weight loss š Avoid excess intake of purine-rich foods, alcoholic beverages and fructose-rich beverages š Increase intake of tart cherry juice or eat 10 cherries a day š Drug therapy: š Drugs to treat acute gout attacks and those that prevent recurrent attacks š Drugs that suppress the immune response to crystal deposition or limit the extent of inflammation 11 Gout Treatment Stage Features Pharmacologic Intervention normal kidney function Acute gout Acute arthritis Glucocorticoids Typically first Colchicine metatarsophalangeal join NSAIDs Excruciating pain Chronic gout Hyperuricemia Allopurinol Development of tophi Probenecid Recurrent attacks of acute Sulfinpyrazone gout 12  Patient Case #1 š A 53-year-old male arrives at urgent care not wearing anything on his left foot. He had awakened that morning with excruciating pain in his great toe. Even the weight of the bed sheet makes him want to scream. He is diagnosed with acute gout. He is prescribed indomethacin for 10 days and within a day of taking the drug, his symptoms are relieved. š Why is indomethacin effective for acute gout attacks? Pharmaceutical Management of Gout Divided into two categories: š Agents that suppress leukocyte recruitment š Agents that Lower Plasma Urate and activation Concentrations š Glucocorticoids š Decrease Uric acid synthesis š Allopurinol š Colchicine š Febuxostat š Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) š Increase uric acid excretion š Probenecid š Sulfinpyrazone š Enhance uric acid metabolism š Rasburicase š Pegloticase 14  Mechanisms of the inflammatory response to urate crystals Glucocorticoids š Agents: prednisone, prednisolone, triamcinolone (intraarticular application) š MOA: Inhibit numerous steps in the inflammatory response š Pregnancy category: D š Adverse Side Effects š Common: edema, weight gain, hypertension, hyperglycemia š Serious: cardiac arrest, impaired wound healing 15 Golan. Figure 49-2 In Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy, 4e, 2017 Anti-mitotic agent Colchicine š MOA: Interferes with microtubule and spindle formation. Reduces neutrophil recruitment to inflamed tissue and neutrophil adhesion. Limits monosodium urate crystal- induced NAPL3 inflammasome activation and subsequent formation of IL-1B and IL-18. š Pregnancy category: C š Adverse Side Effects š Common: diarrhea, nausea, vomiting š Serious: myelosuppression 16 NSAIDS š Agents: Indomethacin, Ibuprofen š MOA: Inhibit cyclooxygenase and thereby inhibit prostaglandin and thromboxane synthesis. Metabolites of arachidonic acid play a role in the inflammatory response to urate crystals in the joint. š Pregnancy category: B š Adverse Side Effects š Common: nausea, vomiting š Serious: Bleeding, salt and water retention 17 Golan. Figure 43-1 In Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy, 4e, 2017  Patient Case #1 š A 53-year-old male arrives at urgent care not wearing anything on his left foot. He had awakened that morning with excruciating pain in his great toe. Even the weight of the bed sheet makes him want to scream. He is diagnosed with acute gout. He is prescribed indomethacin for 10 days and within a day of taking the drug, his symptoms are relieved. š Why is indomethacin effective for acute gout attacks?  Patient Case #1 Continued š A 53-year-old male visits with his primary care physician to follow up about his acute gout diagnosis. His PCP recommends when he has an acute flare to take a high dose of ibuprofen. He continues to have acute flares that are treatable with ibuprofen. š Why is ibuprofen effective for acute gout attacks? š Why would the physician recommend ibuprofen over indomethacin for acute gout attacks?  Patient Case #1 Continued š 10-years later the patient visits his physician indicating the ibuprofen does not relieve the gout flare pain in the left knee or toe. Aspiration of the left knee reveals uric acid crystals. An x-ray of the left knee is normal, but the left toe shows signs of bony erosion of the distal first metatarsal. The patient is started on a 10-day course of prednisone. After finishing the course of prednisone, the patient is prescribed allopurinol to take daily long-term. A prescription for 6 months of daily colchicine is added as well. š How does prednisone work to reduce pain during an acute gout attack? š How does allopurinol act? Will it alter the frequency of the patient’s gout attacks? š Why was colchicine prescribed during the first 6 months of treatment with allopurinol? Xanthine Oxidase Inhibitors š Agents: Allopurinol, febuxostat š MOA: Inhibits xanthine oxidase, the enzyme that converts hypoxanthine to xanthine and xanthine to uric acid; decreased uric acid levels to lead to reduced urate crystal formation š Pregnancy category: B š Adverse Side Effects š Common: pruritus, rash, GI disturbance š Serious: agranulocytosis, aplastic anemia 21 Uricosuric agents š Agents: Probenecid, Sulfinpyrazone š MOA: Increases uric acid (urate) excretion by inhibiting the URAT1 transporter protein in the kidneys to decrease reuptake of uric acid š Pregnancy category: B š Adverse Side Effects š Common: Gastrointestinal disturbances š Serious: bronchoconstriction in asthma š Considerations š Patients lacking the URAT1 anion transporter protein do not respond to uricosuric agents š Low-dose aspirin may antagonize probenecid 22 action Agents enhance Uric Acid Metabolism š Agents: Rasburicase, Pegloticase š MOA: Enzymes that convert sparingly soluble urate to the more soluble compound, allantoin š Adverse Side Effects š Common: Gastrointestinal disturbance š Rasburicase: rash, headache, fever š Pegloticase: chest pain, nasopharyngitis š Black Box Warning for both agents: Anaphylaxis and infusion reactions have been reported to occur during and after administration of pegloticase. 23 Interleukin-1 Inhibitors š Agents: Anakinra š MOA: blocks the biologic activity of interleukin-1 (IL-1) by competitively inhibiting IL-1 binding to the IL-1 type I receptor š Pregnancy category: B š Adverse Side Effects š Common: Injection site reaction š Serious: Anaphylaxis 24  Patient Case #1 š A 53-year-old male arrives at urgent care not wearing anything on his left foot. He had awakened that morning with excruciating pain in his great toe. Even the weight of the bed sheet makes him want to scream. He is diagnosed with acute gout and is started on a high dose of ibuprofen which relieves his symptoms. The patient continues to have acute flares that are treatable with ibuprofen. 10-years later the patient visits his physician indicating the ibuprofen does not relieve the gout flare pain in the left knee or toe. Aspiration of the left knee reveals uric acid crystals. An x- ray of the left knee is normal, but the left toe shows signs of bony erosion of the distal first metatarsal. The patient is started on a 10-day course of prednisone. After finishing the course of prednisone, the patient is prescribed allopurinol to take daily long-term. A prescription for 6 months of daily colchicine is added as well. š Why is ibuprofen effective for acute gout attacks? š How does prednisone work to reduce pain during an acute gout attack? š How does allopurinol act? Will it alter the frequency of the patient’s gout attacks? š Why was colchicine prescribed during the first 6 months of treatment with allopurinol? Summary š The management of gout in patients follows four principles: (1) lowering serum uric acid, (2) providing prophylaxis treatment while initiating urate-lowering therapy, (3) treating gout flares, and (4) optimizing dietary and lifestyle factors as appropriate. 26