Podcast
Questions and Answers
What is allantoin primarily associated with in humans?
What is allantoin primarily associated with in humans?
In what context is allantoin often mentioned concerning its effects?
In what context is allantoin often mentioned concerning its effects?
Which of the following is NOT a known function of allantoin in human tissues?
Which of the following is NOT a known function of allantoin in human tissues?
Which statement about allantoin in humans is accurate?
Which statement about allantoin in humans is accurate?
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What aspect of allantoin's role in humans is often overlooked?
What aspect of allantoin's role in humans is often overlooked?
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What is the maximum time frame within which treatment must be initiated to effectively alleviate acute gout pain?
What is the maximum time frame within which treatment must be initiated to effectively alleviate acute gout pain?
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Which statement correctly describes a characteristic of the drug's mechanism of action?
Which statement correctly describes a characteristic of the drug's mechanism of action?
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What body systems are involved in the excretion of the drug?
What body systems are involved in the excretion of the drug?
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What is a potential effect of the drug when it is teratogenic?
What is a potential effect of the drug when it is teratogenic?
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Which of the following best describes the role of tubulin in the action of the drug?
Which of the following best describes the role of tubulin in the action of the drug?
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Which type of medication is classified as a corticosteroid?
Which type of medication is classified as a corticosteroid?
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What is the primary action of colchicine?
What is the primary action of colchicine?
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Why is colchicine often considered a last-choice medication?
Why is colchicine often considered a last-choice medication?
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Which of the following is NOT a characteristic of tubulin inhibitors?
Which of the following is NOT a characteristic of tubulin inhibitors?
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In what context is colchicine mainly prescribed?
In what context is colchicine mainly prescribed?
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Study Notes
Gout Diagnostic Criteria
- Gout is a metabolic disorder of uric acid, characterized by four criteria
- Increased uric acid level in the blood (Hyperuricemia) > 6 mg%
- Increased uric acid level in urine
- Precipitation of uric acid crystals in joints (metatarsophalangeal joint) leading to acute gouty arthritis
- Swelling (tophi) of cartilage and/or joints
Uric Acid Metabolic Pathway
- Nucleoprotein (DNA-RNA) → Purine → Hypoxanthines → Xanthines → Xanthine oxidase enzyme → Uric acid → Uricase enzyme → Allantoin
- Uric acid precipitates in urine and joints
- Uric acid is a soluble metabolite and doesn't precipitate in tissues
Pathogenesis of Gout
- When serum uric acid increases, monosodium urate crystals are selectively deposited in and around the joint tissue, causing irritation and inflammation.
- PNLs and macrophages phagocytose foreign uric acid crystals causing swelling and inflammation in the articular surface
- Leukocytes die, releasing proteolytic enzymes and inflammatory mediators (IL, PGs) causing severe inflammation
Pathogenesis of Gout (Continued)
- Gout is characterized by hyperuricemia
- Hyperuricemia is due to an imbalance between over-production and under-excretion of uric acid
- Urate crystals are phagocytosed by synoviocytes, which release PGs, lysosomal enzymes, and IL-1
- These mediators cause PMNs to migrate into the joint space, amplifying the inflammatory process
- Macrophages ingest urate crystals and release more inflammatory mediators, including lactic acid, creating a vicious cycle
Classification of Anti-Gout Drugs
- Gout therapy includes hypouricemic drugs (for chronic gout), anti-inflammatory drugs (for acute attack)
- Hypouricemic drugs include uricostatic agents (inhibit UA synthesis) and uricosuric agents (increase UA excretion)
- Uricolytics increase uric acid metabolism
- Examples include: Allopurinol, Febuxostat, Probenecid, Pegloticase
Treatment of Acute Gout Attack
- NSAIDS (Selective or non-selective): all types can be used except small doses of aspirin. Paracetamol is ineffective as it lacks anti-inflammatory properties.
- Corticosteroids are a good alternative when NSAIDs or colchicine are ineffective or in refractory cases. Can be given orally, intravenously, or intramuscularly. Intraarticular administration is appropriate when only one or two joints are affected
- Tubulin inhibitors (Colchicine): a plant alkaloid used for acute gouty arthritis. It has no uricosuric or analgesic effect. It is given orally, has rapid absorption, passes the blood-brain barrier (seizures), and the placental barrier (teratogenic). It's excreted in bile and urine, alleviating acute gout pain within 12 hours. Must be administered within 36 hours of attack onset to be effective
Mechanism of Action of Colchicine
- Colchicine binds to tubulin in PMNs, inhibiting cell division (mitotic blocker). It also reduces the release of inflammatory mediators (LTs) and prevents migration of PMNs to the affected area
- It does not affect uric acid synthesis, excretion, or blood levels
Adverse Effects of Colchicine
- Common side effects include gastrointestinal (GI) tract issues like nausea, vomiting, and diarrhea
- Less common but serious side effects include: hepatotoxicity; nephrotoxicity (hematuria and oliguria); chronic administration causing bone marrow depression (most serious); myopathy; and reversible alopecia (rarest)
Therapeutic Uses of Colchicine
- Colchicine is used to treat acute gout attacks (NSAIDs have largely replaced colchicine because of safety issues with severe diarrhea and delayed action). It's also used to prevent gout. Colchicine is also prescribed for prophylaxis of Familial Mediterranean Fever
Contraindications of Colchicine
- Colchicine is contraindicated during pregnancy
- Caution should be used in patients with hepatic, renal, or cardiovascular diseases
Treatment of Chronic Gout
- Uricostatic agents inhibit uric acid synthesis (xanthine oxidase inhibitors like allopurinol, Febuxostat)
- Uricosuric agents increase uric acid excretion (like Probenecid)
- Uricolytics increase uric acid metabolism (like Pegloticase)
Considerations Before Chronic Gout Treatment
- Initiate urate-lowering therapy with caution, as it can precipitate an acute gout attack due to rapid serum urate concentration changes.
- Use medications to prevent acute attacks (low-dose colchicine, NSAIDs, or corticosteroids) initiated with urate-lowering therapy and continued for at least 6 months.
Treatment Strategies of Chronic Gout
- First-line treatment involves reducing uric acid synthesis by using xanthine oxidase inhibitors
- Second-line treatment involves increasing uric acid excretion by using uricosuric agents
Treatment of Chronic Gout (Continued)
- Uricostatic agents inhibit uric acid synthesis (xanthine oxidase inhibitors, e.g.,allopurinol, febuxostat)
- Uricosuric agents decrease uric acid levels in the blood while increasing levels in urine, hence, advise increased water intake, and creating an alkaline urine (by drinking bicarbonate to prevent precipitation of uric acid)
Allopurinol (Uricostatic Agent)
- Mechanism of action: Competitively inhibits xanthine oxidase, reducing uric acid production
- Pharmacokinetics: Given orally, high absorption, metabolized to an active metabolite in the liver, excreted in feces and urine. Renal impairment may require dose reduction.
- Therapeutic uses: Chronic hyperuricemia in gout, and hyperuricemia secondary to malignancies, particularly post-chemotherapy.
- Adverse Effects: Common skin rash, GI intolerance (N, V, D), gout flare when used with existing acute attacks. Precautions should be taken and given for prophylaxis and not used for existing acute attacks.
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Description
Test your knowledge on the diagnostic criteria and metabolic pathways related to gout. This quiz covers the pathogenesis of the disease and how uric acid plays a role in its development. Ideal for students and healthcare professionals interested in metabolic disorders.
