GOUT

By Prof. Azza El- Medany Dr. Osama Yousf

OBJECTIVES At the end of lectures students should : Define gout Describe outlines of treatment Describe treatment of acute gouty arthritis Describe the mechanism of action , clinical uses & side effects of drugs used in acute attacks

OBJECTIVES ( continue) Classify drugs used in chronic treatment Define each group of drugs Describe the mechanism of action, clinical uses & side effects & drug interactions for drugs used in chronic treatment

Breakdown of product of the body’s purine (nucleic acid) metabolism. What is gout? High blood uric acid level Acute arthritis monosodium urate stone in kidney ♂>♀ Familial metabolic disease Breakdown of product of the body’s purine (nucleic acid) metabolism.

etiology of raised uric acid level Idiopathic decrease in uric acid excretion (75%) Increase uric acid production due to increased cell turn over (tumors), increase uric acid synthesis High dietary purine intake Impaired uric acid excretion secondary to thiazide diuretics, chronic Renal failure

Aaarrrgghhh!!

What is the treatment for gout ?

Clinical stages of Gout

Asymptomatic Stage Acute stage Intercritical stage Chronic stage 1 2 3 4 Chronic stage

ASYMPTOMATIC STAGE urate levels rise in the blood, but produces no symptoms

ACUTE STAGE

INTERCRITICAL STAGE symptom-free intervals between gout episodes. Most people have a second attack from six months to two years, while others are symptom-free for five to 10 years.

CHRONIC STAGE

Broad lines in treatment of gout Non-pharmacologic pharmacologic Acute gouty arthritis Chronic gout(long term treatment)

Non-pharmacologic Therapy

Control….

Acute gouty arthritis NSAIDs colchicine corticosteroid

1. NSAIDs

NSAIDs (Selective or non- selective ) Inhibit pain & inflammation. Inhibit urate crystal phagocytosis by decreasing the migration of granulocytes into the inflammatory area. They are commonly used now for treatment of acute attack or to prevent recurrent attacks with other drugs. ( Except aspirin & paracetamol)

2. Colchicine

Basyir Bin Kamaruzaman (15)

OVERVIEW A plant alkaloid A Selective drug effective only in gouty arthritis Has No analgesic effects

MECHANISM OF ACTIONS Binds to tubulin (microtubular protein ) disrupt cellular function ( migration of granulocytes to affected area Inhibits the synthesis and release of leukotrienes & TNF-α Blocks cell division by binding to mitotic spindles

PHARMACOKINETICS PHAPHARMACOKINETICS Given orally, followed by rapid absorption from the GI tract Reaches peak plasma levels within 2 hours Excreted unchanged in the faeces & urine. Should be used with caution in patients with renal impairment

Treatment for Mediterranean Fever THERAPEUTIC USES Treatment for Mediterranean Fever Colchicine is used as prophylaxis to prevent recurrent attacks in more than 80 percent of patients. The anti-inflammatory activity of colchicine is specific for gout, alleviating the pain within 12 hours

Adverse effects Severe diarrhea ( cause of its restriction in use ) Chronic use alopecia, bone marrow depression, peripheral neuritis, myopathy.

Acute intoxication ( large doses) Burning pain in throat Bloody diarrhea Shock Hematuria C.N.S. depression

Contraindication pregnancy Precaution in hepatic , renal problems

3. Corticosteroids

Chronic gout (long term treatment) 2-Increase excretion of uric acid 1-Inhibition of uric acid synthesis 2-Increase excretion of uric acid

Treatment of Refractory Gout Mammalian uricase enzyme

Inhibition of uric acid synthesis

Xanthine Oxidase Inhibitors

Mechanism of action

ALLOPURINOL-Pharmacokinetics Well absorbed orally (80% ) Metabolized in the liver to oxypurinol which is responsible for most of its urate-lowering effect Given once daily. Drug & its metabolite excreted through the kidney. Dose adjustment is needed in renal impairment

Pharmacokinetics

Therapeutic Uses Treatment of primary hyperuricemia

Hyperuricemia secondary to other conditions such as :

Impaired renal functions.

uric acid stones or nephropathy.

In patients receiving cancer chemotherapy

ALLOPURINOL SIDE EFFECTS & DRUG INTERACTIONS

Side Effects (most common) exacerbation of an acute attack of gout

Maculopopular skin rash

nausea, diarrhea

Side Effects (less common) Body : fever, headache CVS : vasculitis

Thrombocytopenia Epistaxis

Potentiates its action Drug Interactions Inhibits metabolism of oral anticoagulant: ( warfarin ) Potentiates its action

Inhibits metabolism of anticancer drugs : (6-mercaptopurine & azathioprine ) So ,doses of anticancer Must be reduced up to 75%

With ampicillin : Increases frequency of skin rash

Febuxostat Is a new oral non-purine xanthine oxidase (XO) inhibitor. Is structurally different from allopurinol as it lacks purine ring Selective and potent inhibitor of XO than allopurinol Well absorbed orally ( 84%), given once daily Can be given with or without food Metabolized in liver & excreted in urine & feces No dose adjustment is needed in renal impairment

Continue Suitable than allopurinol in patients with impaired renal function as no dose adjustment is required . Used for treatment of chronic hyperuricemia in gout patients Given to patients who do not tolerate allopurinol

Adverse effects Recurrent attacks of acute gout during the first few months of treatment Increase level of liver enzymes Nausea, Diarrhea Headache Numbness of arm or leg

DRUGS INCREASED EXCRETION OF URIC ACID

Uricosuric drugs

1- Probenecid

3- Large doses of aspirin ( more than 5g ) 2- Sulfinpyrazone 3- Large doses of aspirin ( more than 5g )

Mechanism of action of uricosuric drugs Block the active transport sites of the proximal tubules(middle segment ) causing : reduction of Uric acid re-absorption (uric acid excretion

Clinical uses Chronic gout

Warning Urine volume should be maintained at a high level, and urinary pH kept alkaline .

Adverse effects Acute attack of gout Risk of uric acid stone GIT upset Allergic rash

( continue) Nephrotic syndrome ( probenecid) Aplastic anemia ( rare )

DRUG INTERACTIONS Probenecid prolong the action of some antibiotics as: penicillins

Contraindications History of urinary tract stones Impaired renal function Recent acute gout attack Administration of low doses of aspirin

Treatment of Refractory Gout Mammalian uricase enzyme

Modified mammalian uricase enzyme Pegloticase Is a modified mammalian uricase enzyme Converts uric acid to allantoin Given I.V. Infusion peak decline in uric acid level within 24-72 hours

Continue Adverse effects Infusion reactions Anaphylaxis Gout flare Used for the treatment of gout in adult patients refractory to conventional therapy Adverse effects Infusion reactions Anaphylaxis Gout flare Nephrolithiasis Arthralgia, muscle spasm Headache

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