Dr.Rathnakar U.P.MD.DIH.PGDHM

Phamacotherapy of Gout

Gout Metabolic disorder preceded by hyperuricemiaPrecipitation of sodim urate crystals in the

tissues ⇛inflammatory response. . .

Excess uric acid

Sodium

Sodium

urate

Accumulates in Soft tissue

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

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

Clinical presentation of gout

Chronic TophaceousGout 

AcuteGout 

DiagnosisDefinitive diagnosis IN synovial fluid or

Tophaceous material Demonstration of MSU

crystals

Polarized microscopy,

Synovial Fluid Findings

Needle shaped crystals of monosodium urate monohydrate

Engulfed by neutrophils

Drugs used in GoutClassification

Drugs used for acute gout:NSAIDSColchicineCorticosteroids

Drugs used for chronic gout:Uricosurics: Probenecid, SulfinpyrazoneUric acid Synthesis inhibitor: Allopurinol

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

Drugs used in GoutClassification

Drugs used for acute gout:NSAIDSColchicine

Drugs used for chronic gout:

ColchicineObtained from Colchicum autumnale

No analgesic/anti-inflammatory action

No effect on blood uric acid levels

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

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

Spindle poisons:MebendazoleColchicineGriseofulvinVinca AlkaloidsPaclitaxel 

Mitotic spindle is essential for equal partitioning of DNAduring cell division

Pharmacokinetics

Rapid oral absorptionPartly metabolized in liverExcreted in bile-enterohepatic circulation

Ultimately excreted in urine & faeces

Gout-ColchicineAcute:1mg→0.25 mg 3 h till controlled or diarrhoea starts

Dramatic response-Diagnostic

Prophylactic: 0.5 mg/day

Other usesFamilial mediterranean feverPrimary biliary cirrhosisSarcoid arthritis

ADEDiarrhoea(bloody), pain abdomen &

vomitingRespiratory depression, throat pain,

haematuria & oliguriaAgranulocytosis, peripheral neuritis &

myopathy

Nausea

G.I.Disturbances

Diarrhoea

Agranulocytosis

Alopecia

ADE OF COLCHICINE

Drugs used in GoutClassification

Drugs used for acute gout:NSAIDSColchicineCorticosteroids

Drugs used for chronic gout:

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

Drugs used in GoutClassification

Drugs used for acute gout:NSAIDSColchicineCorticosteroids

Drugs used for chronic gout:Uricosurics: Probenecid, SulfinpyrazoneUric acid Synthesis inhibitor: Allopurinol

URATE LOWERING TREATMENT

Who to treat? 1. Tophi 2. Gouty athropathy 3. Radiographic changes of gout 4. Multiple joint involvement 5. Nephrolithiasis

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

Probenecid Probenecid [Decreases plasma concn of UA] [Increases concn of penicillins]

URIC ACID PENICILLIN [Absorption] [Excretion]

Lumen

Renal tubule

TRANSPORTER

Pharmacokinetics

Complete oral absorption90% plasma protein bound

Conjugated in liver & excreted in urine

Plasma t1/2 = 8-10 hrs

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

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

Sulfinpyrazone Uricosuric drugInhibits tubular reabsorption of uric acid

Uricosuric action: additive with Probenecid Antagonised by salicylates

Inhibits platelet aggregation

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

Drugs used in GoutClassification

Drugs used for acute gout:NSAIDSColchicineCorticosteroids

Drugs used for chronic gout:Uricosurics: Probenecid, SulfinpyrazoneUric acid Synthesis inhibitor: Allopurinol

Hypoxanthine

Xanthine

Uric acid

Xanthine oxidase

Xanthine oxidase

Alloxanthine

Allopurinol

Allopurinol

Xanthine oxidase

Pharmacokinetics 80% orally absorbedNot bound to plasma proteins

Metabolized largely to Alloxanthine

Chronic use: inhibits its own metabolism

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

AllopurinolAdverse effects:Hypersensitivity reactions: rashes, fever, malaise & muscle pain; STEVENS JOHNSON SYNDROME

Gastric irritation, headache, nausea & dizziness

Rarely liver damage

AllopurinolContraindications: • Hypersensitive • Pregnant & lactating

mothers • Elderly & children • Liver & kidney disease

AllopurinolOther uses:

Secondary hyperuricemiaTo potentiate 6-mercaptopurine or Azathioprine

Kala-azar: inhibits Leishmania by altering purine metabolism

RasburicaseRecombinant urate-oxidase

Produced by a genetically modified Saccharomyces cerevisiae strain

Lowers urate levels more effectively than allopurinol

RasburicaseIndicated for

With anti cancer therapy in children

Adverse efffects:Hemolysis in -(G6PD)-deficient patients, methemoglobinemia, acute renal failure, and anaphylaxis

Route of administration

SJSallopurinol, diclofenac, fluconazole, valdecoxib, penicillins, barbiturates, sulfonamides, phenytoin, azithromycin, lamotrigine, nevirapine, ibuprofen[8], ethosuximide, carbamazepine

Choi, H. K. et. al. Ann Intern Med 2005;143:499-516

GoutWhat is gout-Purine metabolismInflammation of jointsMOA of inflammationDrugs—Acute and chronic