Pharmacology of Drugs Used in Gout Management PDF

Dr. Asmaa F. Sharif Ph D., JMHPE, MSc., MBBCh College of Medicine – ‫كلية الطب‬ – Course Name and ‫اسم ورقم المقرر‬ 12/7/2024 1 No. ...

Dr. Asmaa F. Sharif Ph D., JMHPE, MSc., MBBCh College of Medicine – ‫كلية الطب‬ – Course Name and ‫اسم ورقم المقرر‬ 12/7/2024 1 No.  At the end of this lecture the student should:  Define gout College of Medicine – ‫كلية الطب‬  Describe outlines of treatment  Describe treatment of acute gouty arthritis  Describe the mechanism of action , clinical uses & side effects of drugs used in acute attacks  Classify drugs used in chronic treatment  Define each group of drugs  Describe the mechanism of action, clinical uses & side effects & drug interactions for drugs used in chronic treatment – Course Name and ‫اسم ورقم المقرر‬ 12/7/2024 2 No.  Gout is a metabolic disorders of uric acid characterized by four criteria: College of Medicine – ‫كلية الطب‬  Increased uric acid level in blood (Hyperuricemia) > 6 mg%.  Increased uric acid level in urine.  Precipitation of uric acid crystals in joints acute gouty arthritis (metatarsophalangeal joint).  Swelling (tophi) of cartilage & or joints. – Course Name and ‫اسم ورقم المقرر‬ 12/7/2024 3 No.  Uric Nucleoprotein (DNA- RNA) acid metabolic Purine pathway College of Medicine – ‫كلية الطب‬ Hypoxanthines Xanthine oxidase enzyme Xanthines Xanthine oxidase enzyme Ppt. in urine and joints Uric acid Uricase enzyme (urate oxidase ) Soluble metabolite In all mammalians except didn’t ppt. in tissues Allantoin humans – Course Name and ‫اسم ورقم المقرر‬ 12/7/2024 4 No.   When serum uric acid increases, monosodium urate crystals are selectively participated in and around the joint College of Medicine – ‫كلية الطب‬ tissue causing irritation and inflammation.  PNLs and macrophages come and phagocytose the foreign uric acid crystals causing swelling and inflammation of the articular surface.  Leukocytes eventually die with the release of proteolytic enzymes and inflammatory mediators (IL, PGs) causing severe inflammation. – Course Name and ‫اسم ورقم المقرر‬ 12/7/2024 5 No. College of Medicine – ‫كلية الطب‬ PMN move by a protein called tubulin 12/7/2024 6 and lactic acid: more and more uric ppt. vicious circle  Gout College of Medicine – ‫كلية الطب‬ therapy Hypouricemic drugs Anti-inflammatory drugs (for acute (for chronic gout) attack) Inhibit UA synthesis Increase UA Increase (Uricostatic Agents) excretion uric acid * NSAIDs metabolism - Allopurinol (Uricosuric Agents) *Corticosteroids. (Uricolytics) - Febuxostat - Probenecid Pegloticase * Colchicine – Course Name and ‫اسم ورقم المقرر‬ 12/7/2024 7 No.  o NSAIDs: (Selective or non- selective )  All types can be used except small dose of aspirin. College of Medicine – ‫كلية الطب‬  Paracetamol is ineffective in gout because its lacks anti- inflammatory properties. o Corticosteroids o Tubulin inhibitor Colchicine (last choice because of its side effects) – Course Name and ‫اسم ورقم المقرر‬ 12/7/2024 8 No.  I) NSAIDs:  They reduce the pain and inflammation.  Treatment of choice for acute gout. i.e. Indomethacin & College of Medicine – ‫كلية الطب‬ Naproxen. II) Corticosteroids:  Good alternative when NSAIDs or colchicine can’t be used or in refractory cases  Can be given Oral, IV, IM  Intraarticular administration of corticosteroids (when only one or two joints are affected) is also appropriate in the acute setting.  Systemic corticosteroid therapy is used for more widespread joint involvement. – Course Name and ‫اسم ورقم المقرر‬ No. 12/7/2024 9  It is a plant alkaloid Used for ttt of acute gouty arthritis only College of Medicine – ‫كلية الطب‬ Has no uricosuric or analgesic effect Pharmacokinetics: o Given Orally, rapid absorption o Pass BBB (seizures). o Pass Placental barrier: teratogenic. o Excreted in bile & urine. o Alleviating the pain of acute gout within 12 hours o Must be administered within maximally 36 hours of attack onset to be effective 12/7/2024 10  Mechanism of action: Bind to tubulin in PMN inhibit College of Medicine – ‫كلية الطب‬ - - - Cell division (mitotic blocker) - - - Inflammatory mediators release (LTs). - - - Migration of PMN to affected area. Does not affect uric acid synthesis or excretion or blood level. 12/7/2024 11  Adverse Effects: College of Medicine – ‫كلية الطب‬ 1- G.I.T.: Nausea, vomiting & Diarrhea. (most common) 2- Hepatotoxicity 3- Nephrotoxicity: Hematuria & Oliguria. 4-Chronic administration: Bone marrow depression (the most serious), myopathy & Reversible alopecia(the rarest) – Course Name and ‫اسم ورقم المقرر‬ 12/7/2024 12 No.  Therapeutic uses  Treatment of acute gout: NSAIDs replaced colchicine use because College of Medicine – ‫كلية الطب‬ of safety issue (severe diarrhea), and relatively delayed action.  Prophylaxis of gout.  Prophylaxis of Familial Mediterranean Fever Contraindications  Pregnancy  Should be used with caution in: Hepatic, renal or cardiovascular diseases. – Course Name and ‫اسم ورقم المقرر‬ 12/7/2024 13 No.   Uricostatic Agents  Uricosuric Agents College of Medicine – ‫كلية الطب‬  Uricolytics drugs – Course Name and ‫اسم ورقم المقرر‬ 12/7/2024 14 No.   Initiation of urate-lowering therapy can precipitate an acute gout attack due to rapid changes in serum urate concentrations College of Medicine – ‫كلية الطب‬  Medications for the prevention of an acute gout attack (low dose colchicine, NSAIDs, or corticosteroids) should be initiated with urate-lowering therapy and continued for at least 6 months 12/7/2024 15  Reduce synthesis of UA by using xanthine College of Medicine – ‫كلية الطب‬ Oxidase inhibitors (uricostatic agents) 1st line Increase excretion of UA by using uricosuric agents 2nd line – Course Name and ‫اسم ورقم المقرر‬ 12/7/2024 16 No.   Uricostatic Agents: inhibit uric acid synthesis: (xanthine oxidase inhibitors) ❑ Allopurinol College of Medicine – ‫كلية الطب‬ ❑ Febuxostat  Uricosuric Agents: ❖ Decrease uric acid level in blood while increased its level in urine: So you should inform the patient to: *increase water intake, **alkaline urine by drinking NaHCO3 to prevent uric acid ppt. ❑ Probenecid.  Uricolytic drugs: increase uric acid metabolism: ❑ Pegloticase – Course Name and ‫اسم ورقم المقرر‬ 12/7/2024 17 No.  Mechanism of action: (Purine like): reduces the production of uric acid by competitively College of Medicine – ‫كلية الطب‬ inhibiting the last two steps in uric acid biosynthesis that are catalyzed by xanthine oxidase Xanthine oxidase alloxanthine - - - of action because both It has long duration the parent compound and its metabolite are potent inhibitors of xanthine oxidase – Course Name and ‫اسم ورقم المقرر‬ 12/7/2024 18 No.  Pharmacokinetic/Therapeutic Action:  Given Orally (80% absorption) College of Medicine – ‫كلية الطب‬  Require dose-reduction in patient with renal impairment.  Metabolized in the liver to active metabolite alloxanthine.  Drug & its metabolite are excreted in the feces & urine. Therapeutic uses:  Treatment of chronic hyperuricemia in patients with gout.  Treatment of hyperuricemia secondary to certain malignancies particularly after chemotherapy. – Course Name and ‫اسم ورقم المقرر‬ 12/7/2024 19 No.  Adverse Effects  Skin rash (most common) College of Medicine – ‫كلية الطب‬  GI intolerance including N,V, D..  Gout flare in the start of ttt. (combine with colchicine). Precautions – Do not give allopurinol during the acute attack of gout. – Give prophylactic cover with NSAIDs or colchicine to avoid exacerbation of gout at the start of therapy – Course Name and ‫اسم ورقم المقرر‬ 12/7/2024 20 No.