pharmacotherapy of gout-mbbs
DESCRIPTION
Dr.U.P.Rathnakar. MD.DIH.PGDHMTRANSCRIPT
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Dr.Rathnakar U.P.MD.DIH.PGDHM
Phamacotherapy of Gout
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Gout Metabolic disorder preceded by hyperuricemiaPrecipitation of sodim urate crystals in the
tissues ⇛inflammatory response. . .
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Excess uric acid
Sodium
Sodium
urate
Accumulates in Soft tissue
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Secondary Hyperuricemia
Leukemias, lymphomas, Polycythemias when treated with
radiation/chemotherapy
Drug induced: thiazides, frusemide, ethacrynic acid, ethambutol, Pyrazinamide.
Ethanol, clofibrate
Diabetic ketoacidosis, lead poisoning, psoriasis
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Hperuricemia MSU crystals depositedIn joints
Phagocytosed by synoviocytes
•Release infl.mediators•[PG,Lysozomal enzymes.IL-1]
•PMN migrate to joint •Phagocytose MSU•RELEASES A GLYCOPROTEIN
Amplifies inflammationLowers pH
Further precipitation of urates
•Phagocytosed by• Macrophages
Sequence of
eventsAt
mol.level
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Clinical presentation of gout
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Chronic TophaceousGout
AcuteGout
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DiagnosisDefinitive diagnosis IN synovial fluid or
Tophaceous material Demonstration of MSU
crystals
Polarized microscopy,
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Synovial Fluid Findings
Needle shaped crystals of monosodium urate monohydrate
Engulfed by neutrophils
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Drugs used in GoutClassification
Drugs used for acute gout:NSAIDSColchicineCorticosteroids
Drugs used for chronic gout:Uricosurics: Probenecid, SulfinpyrazoneUric acid Synthesis inhibitor: Allopurinol
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NSAIDsIndomethacin, naproxen, piroxicam, diclofenac potassium
Except aspirin, salicylates & tolmetin
Inhibit urate crystal phagocytosis & migration of leukocytes → inflamed joint
Not recommended for long term useIndomethacin:50mg QID→ 25mg QID
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Drugs used in GoutClassification
Drugs used for acute gout:NSAIDSColchicine
Drugs used for chronic gout:
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ColchicineObtained from Colchicum autumnale
No analgesic/anti-inflammatory action
No effect on blood uric acid levels
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Hperuricemia MSU crystals depositedIn joints
Phagocytosed by synoviocytes
•Release infl.mediators•[PG,Lysozomal enzymes.IL-1]
•PMN migrate to joint •Phagocytose MSU•RELEASES A GLYCOPROTEIN
Amplifies inflammationLowers pH
Further precipitation of urates
•Phagocytosed by• Macrophages
Sequence of
events
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Colchicine---MOA1. Inhibits release of glycoprotein2. Binds to‘tubulin’ →
depolymerisation/disappearance of microtubules prevents migration of granulocytes
Other actions1. Antimitotic-Metaphase arrest2. Increases gut motility
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Spindle poisons:MebendazoleColchicineGriseofulvinVinca AlkaloidsPaclitaxel
Mitotic spindle is essential for equal partitioning of DNAduring cell division
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Pharmacokinetics
Rapid oral absorptionPartly metabolized in liverExcreted in bile-enterohepatic circulation
Ultimately excreted in urine & faeces
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Gout-ColchicineAcute:1mg→0.25 mg 3 h till controlled or diarrhoea starts
Dramatic response-Diagnostic
Prophylactic: 0.5 mg/day
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Other usesFamilial mediterranean feverPrimary biliary cirrhosisSarcoid arthritis
ADEDiarrhoea(bloody), pain abdomen &
vomitingRespiratory depression, throat pain,
haematuria & oliguriaAgranulocytosis, peripheral neuritis &
myopathy
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Nausea
G.I.Disturbances
Diarrhoea
Agranulocytosis
Alopecia
ADE OF COLCHICINE
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Drugs used in GoutClassification
Drugs used for acute gout:NSAIDSColchicineCorticosteroids
Drugs used for chronic gout:
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Corticosteroids Intraarticular injection of Soluble
steroidsCrystalline preparations should not be
usedIndicated in
Refractory casesIntolerance to NSAIDs or Colchicine
Systemic steroids- Prednisolone- reserved for severe cases
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Drugs used in GoutClassification
Drugs used for acute gout:NSAIDSColchicineCorticosteroids
Drugs used for chronic gout:Uricosurics: Probenecid, SulfinpyrazoneUric acid Synthesis inhibitor: Allopurinol
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URATE LOWERING TREATMENT
Who to treat? 1. Tophi 2. Gouty athropathy 3. Radiographic changes of gout 4. Multiple joint involvement 5. Nephrolithiasis
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ProbenecidCompetitive inhibition of active transport of organic acids at all sites especially at renal tubules
Penicillin ⇨predominantly secreted; minimal absorptionNet effect⇨ probenecid inhibits secretion ⇨⇪blood levels
Uric acid⇨ largely reabsorbedNet effect⇛ Probenecid promotes excretion ⇨⇩blood levels
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Probenecid Probenecid [Decreases plasma concn of UA] [Increases concn of penicillins]
URIC ACID PENICILLIN [Absorption] [Excretion]
Lumen
Renal tubule
TRANSPORTER
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Pharmacokinetics
Complete oral absorption90% plasma protein bound
Conjugated in liver & excreted in urine
Plasma t1/2 = 8-10 hrs
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Drug interactionsProbenecid Inhibits: Excretion of
Penicillins, Cephalosporins, Sulfonamides, Methotrexate,Indomethacin
Inhibits Biliary excretion of Rifampin
Inhibits Secretion of nitrofurantoin ⇛fails to attain anti
bacterial conc in urineUricosuric action of Probenecid is blocked by
salicylates
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Uses: Probenecid 1. Chronic gout:
With plenty of water + alkalinisation of urine:To prevent crystallization of excess urate in urinary tract
Life long treatment is often requiredNot to be started during acute attack; dealt with NSAIDs
No use if kidney is damaged2. Also in Secondary hyperuricemia3. Prolong action of Penicillin/Ampicillin
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Sulfinpyrazone Uricosuric drugInhibits tubular reabsorption of uric acid
Uricosuric action: additive with Probenecid Antagonised by salicylates
Inhibits platelet aggregation
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BenzbromaroneNewer, more potent uricosuric drug
Used in patients allergic or refractory to probenecid or sulfinpyrazone
Patients with renal insufficiencyReversible inhibitor of tubular reabsorption of uric acidADE: Fulminant liver failure
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Drugs used in GoutClassification
Drugs used for acute gout:NSAIDSColchicineCorticosteroids
Drugs used for chronic gout:Uricosurics: Probenecid, SulfinpyrazoneUric acid Synthesis inhibitor: Allopurinol
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Hypoxanthine
Xanthine
Uric acid
Xanthine oxidase
Xanthine oxidase
Alloxanthine
Allopurinol
Allopurinol
Xanthine oxidase
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Pharmacokinetics 80% orally absorbedNot bound to plasma proteins
Metabolized largely to Alloxanthine
Chronic use: inhibits its own metabolism
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Drug interactions of Allopurinol
Inhibits degradation of 6-mercaptopurine & azathioprine
Probenecid shortens t1/2 of alloxanthineAllopurinol prolongs t1/2 of probenecid
Potentiates warfarin & theophyllineAmpicillin + Allopurinol ⇨⇪ rashes
Iron therapy is not recommended
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AllopurinolAdverse effects:Hypersensitivity reactions: rashes, fever, malaise & muscle pain; STEVENS JOHNSON SYNDROME
Gastric irritation, headache, nausea & dizziness
Rarely liver damage
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AllopurinolContraindications: • Hypersensitive • Pregnant & lactating
mothers • Elderly & children • Liver & kidney disease
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AllopurinolOther uses:
Secondary hyperuricemiaTo potentiate 6-mercaptopurine or Azathioprine
Kala-azar: inhibits Leishmania by altering purine metabolism
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RasburicaseRecombinant urate-oxidase
Produced by a genetically modified Saccharomyces cerevisiae strain
Lowers urate levels more effectively than allopurinol
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RasburicaseIndicated for
With anti cancer therapy in children
Adverse efffects:Hemolysis in -(G6PD)-deficient patients, methemoglobinemia, acute renal failure, and anaphylaxis
Route of administration
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SJSallopurinol, diclofenac, fluconazole, valdecoxib, penicillins, barbiturates, sulfonamides, phenytoin, azithromycin, lamotrigine, nevirapine, ibuprofen[8], ethosuximide, carbamazepine
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Choi, H. K. et. al. Ann Intern Med 2005;143:499-516
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GoutWhat is gout-Purine metabolismInflammation of jointsMOA of inflammationDrugs—Acute and chronic
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