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IMSK-_Gout.pdf
- 1. Therapy of Gout SanjayaMani Dixit Assistant Prof of Pharmacology
- 2. Metatarso-phalangeal joint ofgreat toe 2
- 3. Gout • Gout isa kind of arthritis that occurs when uric acid builds up in blood and causes joint inflammation owing to the presence of MSU crystals in the joint and periarticular tissues. • Acute gout is a painful condition that typically affects one joint (Metatarso-phalangeal joint). • Chronic gout is repeated episodes of pain and inflammation, which may involve more than one joint. • Causes: – Uric acid over production (10%) – Diminished renal clearance (90%) Normal Serum Uric Acid Values • Male: 3- 8 mg/dl • Female: 2-7 mg/dl • Rises with age 3 Absent in Humans
- 4. Gout • Gout mayrun in families. • It is more common in men (>5:1), and in women after menopause. – Low water solubility at low pH. • When blood levels are high, it precipitates and deposits in joints, kidney and subcutaneous tissue (tophy). • Tophi are lumps below the skin around joints or in other places. They may drain chalky material. Commonly, they occur on the ear, fingers and toes and around the ankle and elbow. 4 Tophi-(Latin) Stone
- 5. Joints affected MSU crystalspreferentially deposit in • peripheral connective tissues in and around synovial joints, • initially favoring the lower rather then upper limbs • Especially targeting, the MTP joint and then the small joints of hands and feet. As the crystals deposit and enlarge, there is progressive involvement of more proximal sites and potential for cartilage and bone damage is seen with secondary OA. 5
- 6. Gout • If toomuch uric acid builds up in the fluid around the joints (synovial fluid), uric acid crystals form. • These crystals cause the joint to swell up and become inflamed. • Mostly it is observed on the feet, though it also affects the wrists, fingers, elbows, knees, ankles and feet. 6
- 7. Symptoms of Gout: •Asymptomatic stage: – In this stage urate levels increase in the blood but it has no any specific signs and symptoms. • Acute stage: (Requires immediate treatment) – swelling – sudden attack of joint pain – joints feel hot, tender and look dusty red or bruised – Malaise, fever, raised ESR & neutrophils • Chronic stage: – Urate deposits in the cartilage, membranes between the bones, tendons and soft tissues and patient feels painful joints. – Skin over the deposits increase sores and release white pus. – Joint inflexibility, limited motion of affect joint – Causes progressive disability and permanent deformities. 7
- 8. Gout Types MSU gout(Mono sodium Urate) is most common type and is generally simply known as gout; however, other types of gout also exists: 1. HA Gout (Calcium Hydroxyapatite) 2. Calcium Oxalate Gout (Rare) 3. Pseudo Gout/CPPD Arthritis (Common) (CPPD-Calcium pyrophosphate dihydrate) • Clinically indistinguishable symptoms • Definitive diagnosis: Aspiration analysis of synovial effusion- type of microcrystals • Treatment of other types of gout is all symptomatic and similar to MSU Gout – NSAIDs, Colchicine and Glucocorticosteroids. 8
- 9. Secondary hyperuricaemia Disease states •It occurs in different disease states like- – Leukaemias, – Lymphomas, – Polycythaemia, – Especially when treated with chemotherapy or radiation: due to enhanced nucleic acid metabolism and uric acid production. 9
- 10. Secondary hyperuricaemia Drugs thatprecipitate acute gout • Thiazides, frusemide, ethacrynic acid • Ethambutol, pyrazinamide • Levodopa • Cytotoxic drugs • Ethanol, Isotretinoin, salicylate (low), clofibrate, cyclosporin, etc. 10
- 11. Manipulating Serum UricAcid Levels (Allopurinol, febuxostat)
- 12. Therapy A. For acutegout: – NSAIDs: Indomethacin, Naproxen, Piroxicam, Diclofenac • Colchicine • Glucocorticosteroids B. For chronic gout: • Uricosuric drugs: Probenecid, Sufinpyrazone • Uric acid synthesis inhibitors: Allopurinol 12
- 13. NSAIDS • Strong antiinflammatorydrugs like- Indomethacin, Naproxen, Piroxicam, Diclofenac is given in relatively high and quickly repeated doses. • Terminate attack in 12-24 hrs, longer than colchicine, but better tolerated. • Naproxen and piroxicam specifically inhibit chemotactic migration of leucocytes into the inflamed joint. • Even once attack is over, low dose continued till control of hyperuricemia is achieved. • In chronic gout, for initial coverup till effect builds up with other drugs. 13
- 14. Colchicine • An alkaloidaldrug, that suppresses gouty inflammation. M/A • The process of release of glycoprotein, normally following phagocytosis of urate crystals which aggravates inflammation is inhibited. • By binding to fibrillar protein tubulin, it inhibits granulocyte migration into the inflamed joint and thus interrupts vicious cycle. • It also inhibits the mast cell release of histamine. 14
- 15. Colchicine Other actions ofcolchicine are: a) Antimitotic: Causes metaphase arrest: tried for cancer chemotherapy but abandoned due to toxicity. b) Increases gut motility through neural mechanisms • No analgesic or anti-inflammatory actions. Also does not have any effect on blood uric acid levels- does not inhibit synthesis or promote the excretion of uric acid. 15
- 16. Colchicine Use Treatment of acutegout Fastest acting drug in gout, 1mg p/o, increase to 6mg max or till diarrhoea occurs. Toxicity high so NSAIDs preferred. Maintenance dose (0.5-1mg/day) given for 4-8 weeks. Definitive diagnosis of gout As a therapeutic trial for definitive diagnosis of gout, because response to colchicine is specific to gout. Prophylaxis- Low dose 0.5-1mg/day prevents further attacks, NSAIDs preferred. 16
- 17. Colchicine Toxicity Dose related, relativelyhigh toxicity Nausea, vomiting Watery or bloody diarrhoea, abdominal cramps (Drug in intestine and mitosis inhibition of mucosa.) High dose: Kidney damage, Intestinal bleeding, CNS depression Death from muscular paralysis & respiratory failure. Chronic therapy : Not recommended Aplastic anemia, agranulocytosis Myopathy and Alopecia (hair loss) 17
- 18. Corticosteroids • Potent immunosuppressantand anti-inflammatory • Given in refractory cases and in those not tolerating NSAIDs or colchicine. • Intra-articular injection of soluble steroid suppresses the symptoms of acute gout. • Very effective and produce rapid response as colchicine, but reserved for patients with Renal failure/history of peptic ulcer bleeding. • Prednisolone 40-60 mg may be given in one day, followed by tapering doses over few weeks. 18
- 19. Corticosteroids • Prednisolone 4xpotency hydrocortisone • Methyprednisolone slightly more potent than prednisolone • S/E- – Stomach irritation, such as indigestion – Tachycardia, nausea, insomnia, metallic taste – Weight gain, thinning skin, muscle weakness, weakening of bones (osteoporosis), high blood pressure – Oral corticosteoids increase vulnerability to infection by viruses chicken pox, measles. 19
- 20. • In severecases with excruciating pain, an opioid analgesic such as pethidine 100mg IM may be necessary. • Addiction liability prevents repeated use. 20
- 21. Treatment of Chronic Gout 21 Drugsused in Chronic gout should not be given during acute gout . During initial 1-2 months treatment with these drugs attacks of acute gout may precipitate due to fluctuating plasma urate levels. NSAIDs or Colchicine may be required at start.
- 22. URIC ACID SYNTHESISINHIBITOR Allopurinol Purine antimetabolite drug Hypoxanthine anlogue: Lack antineoplastic axn M/A • Inhibitor of xanthine oxidase, enzyme responsible for uric acid synthesis. • It has short T1/2 2 hrs, but it gives active metabolite Alloxanthine T1/2 24 hrs. It is a noncompetitive inhibitor of uric acid synthesis in vivo. • During allopurinol administration, plasma concentration of uric acid is reduced and that of hypoxanthine and xanthine is somewhat increased. In place of uric acid alone all 3 oxipurines which are more water soluble, are excreted in urine. 22
- 23.
- 24. URIC ACID SYNTHESISINHIBITOR Allopurinol Uses • DOC in chronic gout • Used in both over producers and under excretors of uric acid, particularly more severe cases, with tophi or nephropathy. • With long-term allopurinol therapy, tophi gradually disappear & nephropathy is halted, even reversed. • To stop secondary hyperuricaemia. • To potentiate 6-mercaptopurine and azathioprine in cancer therapy. • Inhibits Leishmania (Kala-azar) by altering its purine metabolism, therefore, used as adjuvant to Sodium Stibogluconate in resistant cases. 24
- 25. URIC ACID SYNTHESISINHIBITOR Allopurinol A/E Uncommon Hypersensitivity rxn- rashes Fever, malaise, and muscle pain Renal impairment increases A/Es. Gastric irritation, headache, nausea and dizziness Stevens-Johnsons syndrome rare & serious Rarely liver damage Precautions Drink more fluid C/I Hypersensitive patients Pregnancy and lactation Caution Renal or hepatic disease 25
- 26. NOTE: They canbe hazardous in: • Urate overproducers (>800mg/24hr) • Urine flow consistently < 1ml/min • Creatinine clearance < 50 ml/min • History of renal calculi 26 URICOSURIC DRUGS
- 27. URICOSURIC DRUGS Probenecid It isan agent which promotes the excretion of uric acid in the urine. M/A Uric acid is largely reabsorbed by active transport, and only 10% of filtered load is excreted in urine. Probenecid, being highly lipid soluble organic acid, competitively blocks uric acid’s active reabsorption and causes it to be excreted out. The therapeutic dose needs to be a bit higher, since small doses decrease urate excretion instead. 27
- 28. URICOSURIC DRUGS Probenecid Uses 1. Chronicgout and hyperuricaemia Second line drug, adjuvant to Allopurinol. It gradually lowers blood urate level; arthritis, tophi may take months to resolve. Probenecid and other uricosurics are ineffective in the presence of renal insufficiency (serum creatinine > 2 mg/dl). Plenty of fluids should be given with probenecid to avoid urate crystallization in urinary tract. 2. To prolong penicillin or ampicillin action By enhancing and sustaining their blood levels, e.g. in gonorrhoea. However, penicillin being relatively non-toxic is rather given in high doses and this is not seen much practically. 28
- 29. URICOSURIC DRUGS Probenecid A/E Generally welltolerated. Dyspepsia Rarely rashes and hypersensitivity seen Toxic dose: Convulsions and respiratory failure. Caution Peptic ulcer 29
- 30. URICOSURIC DRUGS Sulfinpyrazone •Uricosuric agent with no analgesic or anti-inflammatory action • Its uricosuric action is additive with probenecid but antagonised by salicylates. • Uricosuric action lasts for 6-10 hours. • It also inhibits platelet aggregation. Uses In chronic gout- results are similar to probenecid Dose 100-200 mg BD, to max 800mg/day. A/E Gastric irritation Rarely rashes and hypersensitivity seen C/I Peptic ulcer 30
- 31. Non-pharmacological intervention • Avoidalcohol and soda • Reduce purine-rich foods especially, sardines, oils, organ meat (liver, kidney, and sweetbreads), legumes (dried beans and peas), gravies, mushrooms, spinach,cauliflower, and baking or brewer's yeast. • Avoid fatty foods such as salad dressings, ice cream, and fried foods. • Eat enough carbohydrates. • If trying to lose weight, lose it slowly. Quick weight loss may cause uric acid kidney stones to form. 31
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