GOUT & ITS TREATMENT by SROTA DAWN

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GOUT & ITS TREATMENT:

BY SROTA DAWN. 1 st year M.PHARM(PHARMACOLOGY) GOUT & ITS TREATMENT

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INTRODUCTION ‘Gout’ is a metabolic disorder characterized by hyperuricemia . Hyperuricemia is a condition when blood SERUM URIC ACID LEVEL gets increased. Uric acid is the end product of purine metabolism

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NORMAL PLASMA URIC ACID CONCENTRATIONS In men 3-7 mg/dl In women 2-6mg/dl Daily excretion of uric acid is about 500 – 700 mg. The prevalence of gout is about 3 per 1,000 persons . mostly affecting males & post-menopausal women however , are as susceptible as man for this disease.

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Gout is a metabolic disease associated with over production of uric acid. Biologically it is synthesized during purine metabolism, Uric acid has 1. Low water solubility. 2 . Especially in low pH When blood levels are high ,it precipitates and deposit as sodium urate crystals on joints, kidneys and subcutaneous tissue( tophy )

Gout: pathophysiology:

Gout: pathophysiology Food intake Cell breakdown Purines Uric acid HYPERURICAEMIA Kidney Soft tissue of the joints Other tissue Ear Overproduction Under excretion

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FACTORS INFLUENCING GOUT FORMATION: HIGH LIVING OVER EATING ALCOHOL CONSUMPTION LEAD POISONING

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Gout is of two types – Primary gout Secondary gout Primary gout : it is an inborn error of metabolism of purine due to over production of uric acid. This is mostly related to increased synthesis of purine nucleotides. 2. Secondary gout : secondary hyperuricemia is due to various disease causing increased synthesis or decreased excretion of uric acid.

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DISORDERS OF PURINE METABOLISM (URIC ACID SYNTHESIS PATHWAY)

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The important metabolic defects are associated with primary gout formation : ENZYMES DIRECTLY INVOLVED IN PURINE SYNTHESIS: PRPP SYNTHATASE : In normal circumstances , PRPP synthetase is under feed back control mechanism by purine nucleotides (ADP and GDP ).This leads to the increased production of purines . PRPP glutamylamidotransferase : The lack of feedback control of this enzyme by purine nucleotides also leads to their elevated synthesis . HGPRT deficiency : This is an enzyme of purine Salvage pathway , and its defects causes lesch – Nyhan syndrome.

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Lesch – Nyhan syndrome. This disorder occurs with increased synthesis of purine nucleotides by 2 fold mechanism Decrease utilization of Purine nucleotides ( hypoxanthine & guanine) The defect in salvage pathway, leads to IMP & GMP

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ENZYMES INDIRECTLY INVOLVED IN PURINE SYNTHESIS: . GLUCOSE 6 – PHOSPHATASE DEFFICIENCY : In von Gierke’s disease, glucose 6-phosphate can not be converted to glucose due to the deficiency of glucose 6- phosphatase. This leads to increased utilization of glucose 6- phosphate by HMP shunt ,resulting in elevated levels of ribose 5- phosphate and PRPP and ultimately leads to purine overproduction. 5.ELIVATION OF GLUTATHIONE REDUCTASE : Increase glutathione reductase generates more NADP+ which is utilized by HMP shunt. This leads to elevated levels of ribose 5- phosphate and PRPP and ultimately leads to purine overproduction.

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PATHWAY OF FORMATION OF GOUT: 1.Precipitation of uric acid crystals on synovial fluid 2. Inflammatory response, chomotactic factors produced 3.Granulocyte migration into the joint, they phagocytose urate crystals and release a glycoprotein which aggregates the inflammation by 4.Increasing lactic acid production from inflammatory cells

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PATHWAY OF FORMATION OF GOUT: 5.local PH reduced 2. more uric acid crystals precipitates in the affected joint . 3. Release lysozomal enzymes which causes joint destruction.

How is Gout Cured?:

How is Gout Cured? No cure Gout can be controlled Diet – eating low purine foods, drinking water Drugs – Allopurinal lowers uric acid production

Therapy for Acute Gouty Arthritis:

Therapy for Acute Gouty Arthritis Colchicine Oral IV Nonsteroidal Anti-inflammatory Agents Corticosteroids Intra-articular IM (ACTH)

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Colchicine : BIOLOGICAL SOURCE : Colchicum autumnale neither analgesic nor anti – inflammatory but suppress the gouty inflammation does not inhibit the synthesis of uric acid does not promote the excretion of uric acid thus has no effect on blood uric acid levels Colchicine inhibits release of the glycoprotein and their by inhibit the following pathway. TOXICITY: Dose related. ADR: 1. Nausea ,vomiting, watery or bloody diarrhoea and abdominal cramps. 2.overdose leads to kidney damage. 3.Chronic therapy with colchichine is not recommended because it causes aplastic anaemia,agranulocytosis,myopathy and loss of hair.

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Nonsteroidal Anti-inflammatory Agents : Strong NSAID s used : indomethacine , naproxen , piroxicam, diclofenac, etoricoxib strong anti-inflammatory action naproxen and piroxicam inhibits chemotactic migration of leucocytes into the inflamed joint. they are not recommended for long term therapy

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Corticosteroids : intraarticular injection of a soluble steroid suppresses symptoms of acute gout. they are very effective and produce nearly as rapid a response as colchicine but are reserved for the patients of renal failure history of peptic ulcer bleed in whom NSAID s are contraindicated. Inhibit PGE 2 and LTB 4 Stabilize lysosomal membranes

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Therapy for Acute Gouty Arthritis When pain and stiffness persist in a joint between attacks, gout has become chronic . Other features are : 1.Hyperuricaemia 2. tophy 3. urate stones in the kidney Two types of drugs are used in this type of chronic gout: uricosuric drugs : 1 . PROBENECID 2 . SULFINPYRAZONE uric acid synthesis inhibitors : ALLOPURINOL

Probenecid/Sulfinpyrazone:

Probenecid/Sulfinpyrazone No analgesic/anti-inflammatory activity. Inhibits uric acid reabsorption . Plenty of water /fluids should be given with probenecid to avoid urate crystallization in urinary tract Increase uric acid excretion in urine. Uses: Chronic gout and hyperuricemia Adverse effects: Hypersensitivity

Allopurinol:

Allopurinol No analgesic/anti-inflammatory activity. Reduces plasma, tissue and urine concentration of uric acid. Reverses of deposition of urate crystals and inhibits urate stone formation.

Drugs used in chronic gout (antihyperuricemic drugs) : sites of action:

Drugs used in chronic gout ( antihyperuricemic drugs) : sites of action Purines Hypoxanthine Xanthine Uric acid Xanthine oxidase Xanthine oxidase PROBENECID SULPFINPYRAZONE - OXYPURINOL - - Overproducers: Allopurinol Underexcretors : Probenecid Sulfinpyrazome ALLOPURINOL -

Allopurinol:

Allopurinol Uses: Chronic gout Tophi Nephropathy Secondary gout Cancer radio/chemotherapy ( coadministered with azathioprine / mercaptopurine )

Allopurinol:

Allopurinol Drug interactions: Azathioprine , mercaptopurine (inhibits degradation) Probenecid (complex interaction) Warfarin,theophyline (inhibit metabolism) Ampicillin (skin rashes) Xanthine oxidase Azathioprine Mercaptopurine Inactive metabolites Allopurinol - Adverse effects: Hypersensitivity

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