Gout Presentation Outline PDF

Title Slide Gout Project Name Under the supervision Gout Team Applied Biochemistry of: Prof. Nahla Osama Prof. Amira Afify 2  Gout Present...

Title Slide Gout Project Name Under the supervision Gout Team Applied Biochemistry of: Prof. Nahla Osama Prof. Amira Afify 2  Gout Presentation Outline Introduction 01 Risk Factors 02 Diagnosis 03 Pathophysiology of hyperuricemia 04 Treatment Approaches 05 Future Aspects 06 Conclusion 07 Reference Slide 08 Gout Overview Video (1) shows an overview about gout 4  Gout Overview triggered by an a type of inflammatory 01 arthritis. 03 accumulation of uric acid in the body. causes joint pain and most commonly affects 02 swelling. 04 the big toe joint. 5  Gout Causes o The buildup of urate crystals in the joints, leading to pain and inflammation. Design Define o Uric acid forms when the body breaks Groups down purines, which are found in red meat, organ meats, seafood, alcohol and fructose-sweetened drinks. o uric acid is filtered by the kidneys into the urine, but when too much is produced, Figure (1) shows the uric acid crystals accumulation. or not enough is excreted, urate crystals form, causing disease 6  Gout Symptoms Joint Affected Progression Inflammation and Pain and Duration and Joint Duration of Attacks Manifestations Primarily affects the big toe Mild discomfort can persist Inflammation leads to but can also occur in other for days or weeks post the swollen, tender, warm, and joints like ankles, knees, elbows, wrists, and fingers. acute pain episode. red joints, limiting the range of motion and Severe pain typically peaks Subsequent, attacks may causing restricted joint within the first 4 to 12 hours. last longer and involve movement. more joints. 7  Chronic Gout Chronic Gout stems from persistent elevated uric acid levels, resulting in frequent acute attacks, joint damage, and potential mobility loss. The symptoms include: Tophi Joint Stiffness Frequent Gout Formation and Attacks Deformities Ongoing joint stiffness, Recurrent episodes of Hard lumps (tophi), under reduced mobility, and intense pain, swelling, and the skin around joints, are possible joint deformities redness in joints, especially caused by uric acid crystal due to long-term in the big toe. deposits. inflammation. 8  Risk Factors 1) Dietary Factors: 3) Medications: a) Consumption of red meat, shellfish, a) Medications affecting uric acid Design and alcohol. Define excretion in the kidneys. Groups b) Fructose-sweetened beverages. b) Immunosuppressants. c) Lack of water intake. c) Medications for high blood pressure 2) Medical Conditions: a) High blood pressure. b) Diabetes. c) Obesity. d) Heart and kidney diseases. e) Metabolic syndrome. 9  Risk Factors 4) Other Risk Factors: 6) Gender Disparity: a) Family history of gout. a) Males are three times more likely to Design b) Previous surgeries. Define develop gout than females. Groups c) Recent injuries. b) After menopause, women's levels of d) Vaccinations. uric acid rise, approaching those of 5) Triggers: men, increasing the risk of gout. a) Dehydration. b) Physical activity. c) Joint injury. 10  Gout Diagnosis 01 02 03 Blood Test Synovial fluid Analysis Imaging Tests 11 1- Blood Test Uric acid test: ○ To check Uric acid levels above 6.8 mg /dl , although people with 01 low levels can also have gout. Urea and creatinine blood test: ○ To check whether reduced kidney function contributes to gout or whether excess uric acid is causing kidney damage. Urinalysis: ○ To check uric acid levels in the urine and assess the risk of kidney stones. 12 2- Synovial fluid Aspirating Synovial Fluid: Involves inserting Analysis a needle into the joint space to extract fluid. Appearance During Flare: The fluid is 02 typically cloudy and often yellow. White Blood Cell Count: Fewer than 50,000 cells/mL indicates non-septic arthritis; higher counts suggest septic arthritis. When it is non-septic arthritis, there is no bacterial infection, but there are crystals. Those crystals, called Monosodium urate crystals (Gold standard), are negatively birefringent, needle-shaped crystals, and yellow in colour when exposed to polarized light microscopy. 13 3- Imaging Tests : X- rays , Ultrasound and CT scans help visualize the affected joints and rule out other 02 conditions that may cause similar symptoms. Because it is very common that patients with psoriatic arthritis to be confused as gout. One of the latest diagnostic methods for gout is CT dual energy, which is non-invasive method that can identify uric acid deposits in the joints, provides a more accurate and detailed view of the affected joint, helping to confirm a gout diagnosis in patients with inconclusive results from traditional tests. 14  Uric Acid Uric acid is the excreted end product of purine catabolism in humans, primates, birds,Define Design and some other Groups animals. Figure (2) shows Uric Acid Structure The rate of uric acid excretion by the normal adult human is about 0.6 g/24 h, arising in part from ingested purines and in part from the turnover of the purine nucleotides of nucleic acids. Figure (3) shows Purine Structure 15  pathophysiology of hyperuricemia The kidneys play a key role in maintaining uric acid metabolic balance. Hyperuricemia is caused by inadequate renal excretion in about 90% of instances and Design Define excessive production in only 10% of cases. Groups Kidneys eliminate about 2/3 of UA produced daily and the remaining 1/3 is removed through the digestive tract. 16 Design Define Groups 17  pathophysiology of hyperuricemia Hyperuricemia can cause crystals of uric acid (or urate) to form. ○ TheseDesign Define crystals can settle in the joints and cause gout, a form of arthritis that can be Groups very painful. ○ They can also settle in the kidneys and form kidney stones. 18 Design Define Groups 19 Pathways for the catabolism of the purine AMP IMP Nucleotidase Nucleotidase Pi NH4 Pi Design Define Groups Adenosine Inosine Adenosine Deaminase (ADA) Purine nucleoside Phosphorylase (PNP) Ribose-1- phosphate Hypoxanthine 20 Design Define Groups 21  Pathways for the catabolism of the purine nucleotides The purine mononucleotides, (d)AMP, (d)GMP, Design Define IMP, and XMP (where the lowercase “d” Groups refers to the deoxyribonucleotide forms) are all catabolized to uric acid. Each mononucleotide is first converted to the phosphate-free nucleoside form through the actions of one of several cytosolic 5′-nucleotidases. 22  Pathways for the catabolism of the purine nucleotides The nitrogen is removed from adenosine Design generating inosine by the critical enzyme, Define Groups adenosine deaminase, ADA. The ribose is removed from the nucleotides by purine nucleoside phosphorylase (PNP) yielding the nucleobases, hypoxanthine, xanthine, and guanine. The nitrogen is removed from guanine by guanine deaminase yielding xanthine. 23  Pathways for the catabolism of the purine nucleotides Hypoxanthine Designand xanthine are thenDefine converted to the terminal product of purine Groups catabolism, uric acid, by the enzyme xanthine oxidase 24  inflammatory response The formation of urate crystals leads to the formationDesign of tophaceous deposits, Define Groups particularly in the joints which precipitate the episodes of gouty arthritis. Gouty arthritis is the most painful manifestation of gout and is caused when Figure (5) shows the engulfment of urate crystals urate crystals interact with neutrophils triggering an inflammatory response. 25 Design Define Groups 26  Colchicine Mechanism of action (MOA): Colchicine inhibits the migration of neutrophils to the site of inflammation so Design Define reduces the inflammatory response.Groups Use: Colchicine treat acute gout flares and can help reduce pain and swelling. Side Effects; Common: Nausea, diarrhea, and abdominal discomfort; Rare but serious: Myelosuppression, Figure (6) shows the colchicine structure neuropathy, and rhabdomyolysis. 27  Colchicine Precaution: it should be Started within the first 24 hours of a gout attack for maximum efficacy; Design Define Early initiation: - Targets peak neutrophil Groups activity during the inflammatory process. - Shortens the duration of the attack; Delayed use (after 24 hours):- Limited benefit as inflammation naturally begins to subside Figure (6) shows the colchicine structure 28  Allopurinol An analogue of hypoxanthine has been used as an antigout drug for more than Design Define half a century Groups has been found to be generally effective in lowering uric acid levels in the blood Figure (7) shows the Allopurinol structure 29  Mechanism of action After Xanthine Oxidase inhibition; the levels of hypoxanthine and Design Define xanthine increase which are more Groups soluble than uric acid and are more readily excreted by the kidneys the production of uric acid decreases reducing the risk of crystal formation and deposition. Figure (8) shows the Allopurinol MOA 30 31  Allopurinol Side Effects Common: gastrointestinal discomfort, liver enzyme abnormalities, Skin rash, Diarrhea and Drowsiness. Design Define Groups Severe: Hypersensitivity reactions, Toxic epidermal necrosis and Mild rash like Stevens-Johnson syndrome. Reducing side effects: Increase fluids, Take it with Figure (9) shows the Allopurinol structure full glass of water, Take it after meal and Use Divided doses. 32  Allopurinol Side Effects Precautions: Drug-Drug Interactions caused by Allopurinol usage; Drugs that increase toxicity Design Define of allopurinol: Thiazide diuretics, ACE inhibitors Groups and Vitamin C; Allopurinol increases toxicity of: Ampicillin, 6-Mercaptopurine and Alcohol. Figure (10) shows the Allopurinol structure 33  Febuxostat xanthine oxidase inhibitor used for chronic hyperuricemia in adults with gout who have inadequate response or intolerance to Design allopurinol. Define Groups Structurally unrelated to uric acid Figure (11) shows Febuxostat Structure 34  Febuxostat Mechanism of Action Febuxostat selectively inhibits xanthine oxidase, an enzyme involved in purine Define Design Groups metabolism to uric acid. By inhibiting xanthine oxidase, Febuxostat reduces uric acid production leads to lower serum urate levels, preventing urate crystal formation in joints for chronic gout management. Figure (12) shows Febuxostat mechanism of action 35  Febuxostat Side Effects liver problems nausea Design Define Groups gout flares joint pain Figure (13) shows liver damage rash If the patient has a history of stroke, liver, kidney, or heart disease or is pregnant, planning to be pregnant, breastfeeding or planning to breastfeed, the physician should be told before taking febuxostat. Precaution: the drug shouldn’t be stopped suddenly. 36  Uricosuric Agents MOA: Uricosuric agents work by increasing the renal excretion of uric acid, thereby lowering uric acid levels in the blood. They Design Define Groups inhibit the reabsorption of uric acid in the kidneys. Uricosuric agents like probenecid are considered second line treatment with patients who cannot tolerate xanthine oxidase inhibitors like allopurinol or Figure (14) shows Gout treatments mechanism of action febuxostat. 37