Pharmacotherapy Of Gout-mbbs

Phamacotherapy of Gout Dr.Rathnakar U.P. MD.DIH.PGDHM

Gout Metabolic disorder preceded by hyperuricemia Precipitation of sodim urate crystals in the

tissues ⇛inflammatory response .

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Exces s uric acid

Accumulate s in Soft tissue

Sodiu m Sodiu m urate

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 deposited In joints

Phagocytosed by synoviocytes

•Release infl.mediators •[PG,Lysozomal enzymes.IL-1] •Phagocytosed by • Macrophages

Sequenc e of events At mol.level

•PMN migrate to joint •Phagocytose MSU •RELEASES A GLYCOPROTEIN Amplifies inflammation Lowers pH

Further precipitation of urates

Clinical presentation of gout

Acute Gout

Chronic Tophaceous Gout

Diagnosis  Definitive 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 Gout Classification Drugs used for acute gout: NSAIDS Colchicine

Corticosteroids Drugs used for chronic gout: Uricosurics: Probenecid, Sulfinpyrazone

Uric acid Synthesis inhibitor: Allopurinol

NSAIDs Indomethacin, naproxen, piroxicam,

diclofenac potassium Except aspirin, salicylates & tolmetin Inhibit urate crystal phagocytosis & migration of leukocytes → inflamed joint Not recommended for long term use Indomethacin: 50mg QID→ 25mg QID

Drugs used in Gout Classification Drugs used for acute gout: NSAIDS Colchicine

Drugs used for chronic gout:

Colchicine

Obtained from

Colchicum autumnale No analgesic/antiinflammatory action No effect on blood uric acid levels

Hperuricemia

MSU crystals deposited In joints

Phagocytosed by synoviocytes

•Release infl.mediators •[PG,Lysozomal enzymes.IL-1] •Phagocytosed by • Macrophages

Sequen ce of events

•PMN migrate to joint •Phagocytose MSU •RELEASES A GLYCOPROTEIN Amplifies inflammation Lowers pH

Further precipitation of urates

Colchicine---MOA Inhibits release of glycoprotein Binds to‘tubulin’ → depolymerisation/disappearance of microtubules prevents migration of granulocytes Other actions Antimitotic-Metaphase arrest Increases gut motility

Spindle poisons: Mebendazole Colchicine Griseofulvin Vinca Alkaloids Paclitaxel

Mitotic spindle is essential for equal partitioning of DNA during cell division

Pharmacokinetics Rapid oral absorption Partly metabolized in liver Excreted in bile-

enterohepatic circulation Ultimately excreted in urine & faeces

Gout-Colchicine Acute:

1mg→0.25 mg 3 h till

controlled or diarrhoea starts Dramatic response-Diagnostic Prophylactic: 0.5 mg/day

Other uses

Familial mediterranean fever Primary biliary cirrhosis Sarcoid arthritis

ADE Diarrhoea(bloody), pain abdomen & vomiting Respiratory depression, throat pain, haematuria & oliguria Agranulocytosis, peripheral neuritis & myopathy

ADE OF COLCHICINE

Nausea G.I.Disturbances Diarrhoea

Agranulocytosis Alopecia

Drugs used in Gout Classification Drugs used for acute gout: NSAIDS Colchicine

Corticosteroids Drugs used for chronic gout:

Corticosteroids Intraarticular injection of Soluble

steroids Crystalline preparations should not be used Indicated in Refractory cases Intolerance to NSAIDs or Colchicine Systemic steroids- Prednisolonereserved for severe cases

Drugs used in Gout Classification Drugs used for acute gout: NSAIDS Colchicine

Corticosteroids Drugs used for chronic gout: Uricosurics: Probenecid, Sulfinpyrazone

Uric 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

Probenecid Competitive inhibition of active

transport of organic acids at all sites especially at renal tubules Penicillin ⇨predominantly secreted; minimal absorption

Net effect⇨ probenecid inhibits secretion

⇨⇪blood levels

Uric acid⇨ largely reabsorbed Net effect⇛ Probenecid promotes excretion ⇨⇩blood levels

Probenecid [Decreases plasma concn of UA]

URIC ACID [Absorption]

Probenecid [Increases concn of penicillins]

TRANSPORTER

Lumen

Renal tubule

PENICILLIN [Excretion]

Pharmacokinetics Complete oral absorption 90% plasma protein bound Conjugated in liver &

excreted in urine Plasma t1/2 = 8-10 hrs

Drug interactions

Probenecid Inhibits: Excretion of Penicillins, Cephalosporins, Sulfonamides, Methotrexate,Indomethacin

Inhibits Biliary excretion of Rifampin Inhibits Secretion of nitrofurantoin ⇛fails to attain anti

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 required Not to be started during acute attack; dealt with NSAIDs No use if kidney is damaged 2. Also in Secondary hyperuricemia 3. Prolong action of Penicillin/Ampicillin

Sulfinpyrazone Uricosuric drug Inhibits tubular reabsorption of

uric acid Uricosuric action: additive with Probenecid  Antagonised by salicylates Inhibits platelet aggregation

Benzbromarone Newer, more potent uricosuric drug Used in patients allergic or refractory to

probenecid or sulfinpyrazone Patients with renal insufficiency Reversible inhibitor of tubular reabsorption of uric acid ADE: Fulminant liver failure

Drugs used in Gout Classification Drugs used for acute gout: NSAIDS Colchicine

Corticosteroids Drugs used for chronic gout: Uricosurics: Probenecid, Sulfinpyrazone

Uric acid Synthesis inhibitor: Allopurinol

Hypoxanthine

Allopurinol Xanthine oxidase

Xanthine oxidase Xanthine

Alloxanthine Xanthine oxidase

Allopurinol

Uric acid

Pharmacokinetics

80% orally absorbed Not 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 alloxanthine Allopurinol prolongs t1/2 of probenecid Potentiates warfarin & theophylline Ampicillin + Allopurinol ⇨⇪ rashes Iron therapy is not recommended

Allopurinol Adverse effects: Hypersensitivity reactions: rashes, fever, malaise & muscle pain; STEVENS JOHNSON SYNDROME Gastric irritation, headache, nausea & dizziness 

Allopurinol Contraindications: • Hypersensitive • Pregnant & lactating mothers • Elderly & children • Liver & kidney disease

Allopurinol Other uses:

Secondary hyperuricemia To potentiate 6-

mercaptopurine or Azathioprine Kala-azar: inhibits Leishmania by altering purine metabolism

Rasburicase Recombinant urate-

oxidase Produced by a genetically modified Saccharomyces cerevisiae strain Lowers urate levels more effectively than allopurinol

Rasburicase Indicated for  With anti cancer therapy in

children Adverse efffects: Hemolysis in -(G6PD)-

deficient patients, methemoglobinemia, acute renal failure, and

SJS allopurinol, 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

Gout What is gout-Purine metabolism Inflammation of joints MOA of inflammation Drugs—Acute and chronic