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

High blood uric acid levelAcute arthritisurate stone in kidney ♂>♀ Familial metabolic disease Breakdo wn of product of the body’s purine (nucleic acid) metaboli sm.

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 ?

DRUGS USED IN TEATMENT OF GOUT 1 st therapeutic strategy for gout involve lowering the uric acid level below the saturation point (<6 mg/dL), thus preventing the deposition of urate crystals. This can be done by: 1.Decreasing uric acid synthesis 2.Increasing uric acid excretion 1 st therapeutic strategy for gout involve lowering the uric acid level below the saturation point (<6 mg/dL), thus preventing the deposition of urate crystals. This can be done by: 1.Decreasing uric acid synthesis 2.Increasing uric acid excretion

2 nd strategy include 1. Inhibiting leukocyte entry into the affected joint 2- Administration of analgesic & anti- inflammatory drugs

Clinical stages of Gout

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

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

ACUTE 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. INTERCRITICAL STAGE

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 NSAIDscolchicinecorticosteroid

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 used only for the treatment of acute gouty arthritis Has No analgesic effects

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

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

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 acute gout, alleviating the pain within 12 hours

Adverse effects Diarrhea is a common adverse effect. Nausea,vomiting,abdominal cramps. 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 Should be used with caution in hepatic, renal or cardiovascular diseases.

3. Corticosteroids

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

3- Recombinant mammalian uricase enzyme Chronic treatment ( cont.)

Inhibition of uric acid synthesis

Xanthine Oxidase Inhibitors

Mechanism of action

Pharmacokinetics of allopurinol 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

Drug Interactions With oral anticoagulant: Such as warfarin Potentiates its action ( inhibits its metabolism)

With anticancer drugs : 6-mercaptopurine and azathioprine Allopurinol inhibits their metabolism 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

Uricosuric drugs

Probenecid

Large doses of aspirin ( more than 5g ) Sulfinpyrazone

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 ( not common )

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

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

Recombinant mammalian uricase Pegloticase Uric acid specific enzyme which is a recombinant modified mammalian uricase enzyme Converts uric acid to allantoin Given I.V. Infusion  peak decline in uric acid level within hours

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

THANK YOU