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th GOUT, MOA :
Colchicine, Therapeutic Uses
Colchicine,…
GOUT
- Metabolic disorder, high levels of uric acid in blood
- Leads to deposition of uric acid crystals in tissues, joints, kidney.
- Therapeutic strategies- lowering uric acid levels below saturation point- 6mg/ml
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Hyperuricaemia**
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Mutations of one of the renal URATs, URAT-1,
Risk factors
- Male sex, diuretic
- alcohol intake, obesity
- Hypertension, consumption of sweetened beverages,
- red meat, and certain types of seafood
Pathophysiology
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D
Drugs that act by inhibition of urate formation-Allopurinol,
febuxostat)
Augmentation of urate excretion -Probenecid
Drugs that relieve inflammation and pain- NSAIDs, colchicine, glucocorticoids
Drugs that prevent inflammatory responses to crystals -Colchicine , NSAIDs
ACUTE GOUT -Treatment
- NSAID
- Colchicine,
- Glucocorticoids
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Febuxostat
ADR - Abdominal pain, diarrhea, headache,
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Antacid-MgoH,AloH- delay absorption
Uric acid synthesis inhibitor-Febuxostat
XO inhibitor
* Rapid oral absorption,(tmax) approximately 1 hour
- Use in long-term management of hyperuricemia
*Not indicated in malignancy associated hyperuricaemia
Uricase * Pegloticase
- pegylated uricase (urate oxidase)
- catalyzes the enzymatic oxidation of uric acid into allantoin, a more soluble and inactive metabolite
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vomiting, nausea, chest pain, constipation, diarrhea, and erythema, pruritus
USES-
Treatment of severe gout,
-refractory, chronic gout
_ when use of other urate-lowering therapies is contraindicated.
infusion every 2 week
- ↓ Blood urate within hours of initial administration
- Antibody development
Rasburicase -Uricase
Hemolysis in G6PD-deficient patients, methemoglobinemia,
acute renal failure, and anaphylaxis
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- indicated - in pediatric and adult patients with leukemia, lymphoma, and solid tumor malignancies- receiving anticancer therapy
- ↓ Uric acid levels within hours of initial administration
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MOA :
Colchicine
Limits
monosodium urate crystal–induced NLRP3 inflammasome activation subsequent formation of IL-1β and IL-18
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Antimitotic effects, arresting cell division in G1
Depolymerization of microtubules-reduces neutrophil
recruitment to inflamed tissue and neutrophil adhesion
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Individualized - based on age, renal and hepatic function, concomitant use of other medications, and disease severity.
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Acute Gout
- given within 24 h of attack onset. Pain, swelling, and redness abate within 12 h and are completely gone within 48 to 72 h.
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ADR-
- Nausea, vomiting, diarrhea, and abdominal pain
- Chronic therapy : Myelosuppression, leukopenia, granulocytopenia, thrombopenia, aplastic anemia ,rhabdomyolysis.
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Corticosteroids:
Intra-articular injection -Triamcinolone acetonide
- Systemic steroids Prednisolone
Reserved for patients
- with renal failure
- peptic ulcer bleed
- responding or not tolerating NSAIDs
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Colchicine -Source- Colchicum autumnale,
- oldest available therapies for acute gout
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Lesinurad
- Gout in patients who have not achieved the target
serum uric acid levels with XO inhibitor alone
- Substrate of the highly polymorphic CYP2C9; caution needed in CYP2C9 poor metabolizers
- Must be used together with XO inhibitor due to renal failure risk
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NSAID
- Effective in terminating the attack within 12-24hrs
- Naproxen, Piroxicam, Diclofenac, Indomethacin
- Effective in terminating the attack within 12-24hrs
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CHRONIC GOUT -Treatment
- Urostatic- Allopurinol,Febuxostat, Pegloticase, Rasburicase
- Uricosuric - Probenecid, Benzbromarone