Download to read offline
More Related Content
Similar to ANTI GOUT DRUGS.....pptx
More from RupaSingh83
![lecture-4 [Autosaved].pptx](https://cdn.slidesharecdn.com/ss_thumbnails/lecture-4autosaved-230730161044-605918a6-thumbnail.jpg?width=640&height=640&fit=bounds)
ANTI GOUT DRUGS.....pptx
- 1.
- 2. Introduction To Gout Defination:Gout is metabolic disease in which plasma urate concentration get increased (hyperuricaemia), ( Normal urate level:3.5 to 7.2 mg/dl). Gout is a common and complex form of arthritis that can affect anyone. It's characterized by sudden, severe attacks of pain, swelling, redness and tenderness in the joints, often the joint at the base of the big toe. 2 Ref: https://curearthritis.org/gout/
- 3. Causes • Uric acidis product of purine metabolism at low pH (acidic) has low water solubility. When urate level increases in blood it gets precipitates and deposits in joints, kidney and cutaneous tissue which is called as tophy. • An excess of uric acid, measured in the plasma as sodium urate, constitutes hyperuricaemia. • This excess may be caused by an overproduction or under excretion of urate. It is influenced by genetic and environmental factors and may be classified as primary (mainly idiopathic) or secondary.
- 4. Causes: 4 ⚫ Overdrinking ofalcoholic beverages, especially beer, or purine-rich foods. ⚫ Leukaemia's, lymphomas, polycythaemia condition treated with chemotherapy radiation causes enhanced nucleic acid metabolism and uric acid production. An increase in urate production may be caused by excessive dietary purine intake, certain cancers or their treatment, or, more rarely, enzyme defects of purine metabolism.
- 5. PATHOPHYSIOLOGY The uric acidis a waste product formed from the degradation of purines through the purines degradation pathway. Purines → xanthine uric acid If there is abnormal production and/or excretion of uric acid it will cause deposition of Monosodium Urate Crystals(MUC) in joints and this will initiate the inflammation and cause gout.
- 6. 9/12/2019 7 * Processof gouty inflammation- Precipitation of urate crystals in synovial fluid Start inflammatory response By producing Chemotactic factors Migration of granulocytes in to joints Which phagocytose (engulf) urate crystals Release glycoprotein Increases lactic acid production form inflamed cell Decreases PH More urate crystals get precipitate and affect joint Release lysosomal enzyme Joint destruction Aggrevates/ Worsen inflammatory condition
- 8. Antigout drugs These arethe drugs which are used in treatment of gout condition which are acts by one of the following mechanism: By ⚫Inhibiting Uric acid synthesis ( Allopurinol). ⚫Increasing Uric acid excretion (Probencid, Sufinpyazone). ⚫Inhibiting leukocyte migration toward joint (Colchicine). ⚫Providing general NSAID’s action (Glucocorticoids). 8
- 9. Classification For acute gout:sudden onset of severe inflammation in a small joint due to precipitating of urate crystal in the joint space. Drugs used are - NSAID’s, Colchicine, Glucocorticoids. For chronic gout/ hyperuricaemia: Chronic gout is the repeated episodes of pain and inflammation. More than one joint may be affected. Ex- 1. Uricosurics agent : Probenecid, Sulfinpyrazone, 2. Uricacidsynthesisinhibitor : Allopurinol
- 10. 1. NSAID’s drugs 1 0 ⚫Various drugs used are indomethacin, naproxen, piroxicam, diclofenac or etoricoxib given at high and repeated dose to terminate attack. ⚫ Produces responses slow as compared to colchicine but well tolerated so more preferred than colchicine. ⚫ Naproxen, piroxicam inhibits chemotactic migration of leucocytes into the inflamed joint. ⚫ Should be avoid in: GI ulcer, Bleeding or perforation, Renal insufficiency , Heart failure , Use of oral anticoagulants
- 11. MECHANISM OF ACTION •COX inhibitors cause inhibition of COX enzyme and inhibits conversion of arachidonic acid into PGG2 later PGG2 to PGH 2, PGI2, PGE2, PGF2α and PGD2. So inhibits pain sensation-Analgesic action, decreased tissue edema- Anti inflammatory action. • Inhibits pain sensation-Analgesic action. • Reduced capillary permeability, decreased tissue edema-Anti inflammatory action. • These release Prostaglandins which are responsible for inflammation, pain etc.
- 13. . Therapeutic uses: • AcuteGout Adverse effect: • Nausea • Vomiting • Constipation • Diarrhea • Dizziness • Edema • Kidney failure • Ulcers.
- 14. 2. Colchicine 1 4 ⚫ Alkaloidfrom Colchicum autumnale / autumn crocus found as antigoute in 1763 and isolated as pure form in 1820. ⚫ Is neither anti-inflammatory or analgesic activity but used specifically in treatment of gouty inflammation. ⚫ .It does not inhibit the synthesis or promote the excretion of uric acid, and has no effect on blood uric acid levels.
- 15. MECHANISM OF ACTION Colchicineaccumulates in white blood cells and affects them in a variety of ways - decreasing motility, mobilization (especially chemotaxis), and adhesion. •Inhibits microtubule polymerization by binding to its constitutive protein, tubulin. As availability of tubulin is essential to mitosis, colchicine may inhibit mitosis •Inhibits activation and migration of neutrophils to sites of inflammation. OR •COLCHICINE: produces its anti-inflammatory effects by binding to the intracellular protein tubulin ,thereby preventing its polymerization into microtubules (arresting neutrophil motility) and leading to the inhibition of leukocyte migration .
- 16. * Mechanism ofaction Colchicine: Start inflammatory response By producing Chemotactic factors Migration of granulocytes in to joints Symptomatic relief for gout Precipitation of urate crystals in synovial fluid Colchicine Bind to fibrillar protein tubulin Depolymerisation of microtubules Decreases cell motility Prevent 16
- 17. • PHARMACOKINETICS : •Absorption: absorbed orally and reaches peak plasma levels with in 2 hrs. • Distribution: Uniform. • Metabolism:Liver • Elimination: bile-undergoes enterohepatic circulation, Urine & faeces
- 18. * Toxicity ofColchicine: High and dose related. At therapeutic dose: Nausea, vomiting, watery or bloody diarrhoea and abdominal cramps. Accumulation of the drug in intestine and inhibition of mitosis . In overdose: colchicine produces kidney damage, CNS depression, intestinal bleeding; death is due to muscular paralysis and respiratory failure. Chronic therapy: Not recommended because it causes aplastic anaemia, agranulocytosis and loss of hair. 18
- 19. 9/12/2019 1 * Druginteraction with other drug: Colchicine shows 1 interaction with; Sr . No. Category of drug Example from class Interaction 1. Cholesterol drugs atorvastatin, fluvastatin, lovastatin, gemfibrozil Serious muscle damage. 2. Antiarrhythmic drug. Digoxin, 3. HIV drugs, indinavir, atazanavir, nelfinavir, saquinavir, or ritonavir. 4. Antidepressressants nefazodone. 5. Antibiotics, clarithromycin or telithromycin 6. Antifungal drugs ketoconazole or itraconazole. Increases concentrationof colchicine 7. Calcium channel blocker verapamil or diltiazem stomach pain, constipation, diarrhea, nausea, or vomiting.
- 20. * Use ofColchicine: 20 1. Treatment of acute gout: Best drug to control an acute attack of gout, 1 mg orally followed by 0.25 mg 1-3 hourly till control of the attack. 2.Prophylaxis condition of gout: Colchicine 0.6-1 mg/day prevent gout attack but now a days NSAID’s are preferred.
- 21. ADVERSE EFFECTS: 1. diarrhea,Nausea , Vomiting and abdominal pain. 2. Rarely causse hair loss and bone marrow depression as well as peripheral neuritis and myopathy.
- 22. 3. Corticosteroid 22 ⚫ Theuse of corticosteroids is often suggested for elderly patients with chronic tophaceous gout. ⚫ Corticosteroids decrease the pain, swelling, redness and (inflammation) of gout. ⚫ Intra-articular inj. : those not tolerating NSAIDs/Colchicine ⚫ But Corticosteroids are used only for patients suffering from renal failure or peptic ulcer( Bcause NSAID’s are contraindicated). ⚫ Risk of rebound of attack is observed on drug withdrawal. ⚫ Example; Prednisolone 40-60 mg given once a day.
- 23. URICOSURIC AGENTS • Theuricosuric drugs are anions that are somewhat similar to urate in structure ,therefore they can compete with uric acid for transport sites. • Small doses of uricosuric agents will actually decrease the total excretion of urate by inhibiting its tubular secretion. • And at high dosages these same drugs increases uric acid elimination by unhibiting its proximal tubular reabsorption • The two most clinically important uricosuric drugs PROBENECID and SULFINPYRAZONE are organic acids • The initial phase of therapy with uricosuric drugs is the most dangerous period, until Uricosuric drugs level build up sufficiently to fully inhibit uric acid reabsorption as well as secretion , there may be a temporary increase in uric acid blood levels that significantlyincreases the risk of an acute gouty attack
- 24. • Therefore ,itis wise to begin therapy with the administration of small amts of colchicine before adding a uricosuric drug to the therapeutic regimen. • In addition , the initial rise in urinary uric concentrations during uricosuric drug therapy maya result in renal stone formation. • PROBENECID: • Mechanism: Blocks tubular reabsorption of uric acid & enhances urine uric acid excretion • Probenecid inhibits Urate Transporters (URAT1) in the apical membrane of the proximal tubule • It also inhibits organic acid transporter(OAT)→↑plasma concentration of penicilin • Dose of probenecid : 0.5 gm orally daily in divided doses, progressing to 1 gm daily after 1 week. • It should be given in divided dose with food to reduce adverse GIT effects
- 25. 4. Probenecid Uric acid Reabsorbedby active transport ⚫ Lipid soluble organic acid developed in 1951. *Mechanism of action Probenecid: Probenecid Active transport of organic acid OATP ( organic anion transporting polypeptide receptor) Block 25 By Blocking Inhibit Causes excretion
- 26. *Pharmacokinetics: ⚫ Absorption: Rapidorally. ⚫ Distribution: 90% bound to plasma protein ⚫ Metabolism: Liver ⚫ Elimination: Urine. *Drug interaction with other drug: Probenecid shows interaction with; 26 Sr . No. Category of drug Example from class Interaction 1. Antibiotics penicillins, cephalosporins, sulfonamides, Inhibits the urinary excretion 2. NSAID’s Indomethacin, salicylates 3. Antibiotics rifampicin. Biliary excretion 4. Antimicrobial nitrofurantoin Inhibits tubular secretion of drug
- 27. * Toxicity ofProbenecid : Dyspepsia (indigestion). Rashes and other hypersensitivity . Toxic doses cause convulsions and respiratory failure. * Use of Probenecid: Chronic gout and hyperuricaemia: ⚫ second line or adjunct drug to allopurinol. ⚫ 0.25 g-0.5g BD gradually lower blood urate level along with arthritis, tophi and other lesions but ineffective during renal insufficiency. ⚫ Plenty of fluids should be given with probenecid to avoid urate crystallization in urinary tract. Prolong drug action: ⚫ Probenecid is also used to prolong penicillin or ampicillin action by enhancing and sustaining their blood levels, e.g. in gonorrhoea, Subacute bacterial endocarditis (SABE). 27
- 28. 5. Sulfinpyrazone ⚫ Itis a pyrazolone derivative related to phenylbutazone having consistent uricosuric action. ⚫ Not having anti-inflammatory or analgesic activity but used specifically in treatment of gouty inflammation. * Mechanism of action Sulfinpyrazone: • It inhibits tubular reabsorption of uric acid • Also inhibits platelet aggregation. * Pharmacokinetics: • Absorption: Rapid orally. • Distribution: 98% bound to plasma protein. • Elimination: active secretion in proximal tubule Urine. 28
- 29. * Adverse effectof Sulfinpyrazone: ⚫ Gastric irritation so contraindicated in patients with peptic ulcer. ⚫ Rashes and other hypersensitivity reactions. ⚫ At overdose convulsions, coma, anaemia, jaundice, and ulceration. * Use of Sulfinpyrazone: Used in treatment of chronic gout 100-200mg BD *Drug interaction with other drug: Sulfinpyrazone shows interaction with; 29 Sr . No. Category of drug Example from class Interaction 1. oral anticoagulant warfarin increase the effects 2. tolbutamide 3. Anti asthmatic theophylline worsening asthma 4. Calcium channel blocker verapamil high blood pressure or an irregular heartbeat.
- 30. URIC ACID SYNTHESISINHIBITOR Allopurinol : is the drug of choice in the treatment of chronic tophaceous gout and is especially useful in patients whose treatment is complicated by renal insufficiency. • it is alternative to increasing uric acid excretion in the treatment of gout is to reduce its synthesis by inhibiting xanthine oxidase with allopurinol
- 31. MOA • Nucleic acidsare converted to xanthine or hypoxanthine and oxidized to uric acid. • Allopurinol is contrast to the uricosuric drugs , reduces serum urate levels through a competitive inhibition of uric acid synthesis rather than by impairing renal urate re absorption. • This action is accomplished by inhibiting XANTHINE OXIDASE, the enzyme involved in the metabolism of hypoxanthine and xanthine to uric acid. • After enzyme inhibition , the urinary and blood concentrations of uric acid are greatly reduced and there is a simultaneous increase in the excretion of more soluble uric acid precursors, xanthine and hypoxanthine.
- 32. 6. Allopurinol Uric acid xanthine ⚫This hypoxanthine analogue was synthesized a purine antimetabolite for cancer chemotherapy it had no antineoplastic activity. ⚫ It has substrate as well as inhibitor of xanthine oxidase, the enzyme responsible for uric acid synthesis. Allopurinol Hypoxanthine Alloxanthene Xanthene oxidase Xanthene oxidase Xanthene oxidase Inhibit both steps 32
- 33. * Pharmacokinetics: • Absorption:Rapid orally.(80%) • Distribution: Not bound to plasma protein. • Metabolism: During chronic administration inhibit self metabolism. • Elimination: 1/3 excreted as unchanged form in urine. *Drug interaction with other drug: Allopurinol shows interaction with; 33 Sr . No. Category of drug Example from class Interaction 1. Anticancer f 6-mercaptopurin & azathioprine Allopurinol prevent degradation of all drugs 2. Uricosurics Probenecid kidney or liver disease 3. Anti asthmatic theophylline skin rashes 4. Haematinics Iron therapy mobilization of hepatic iron stores
- 34. * Adverse effectof Allopurinol: ⚫ Gastrointestinal intolerance , including nausea, vomiting and diarrhea , may occur. ⚫ Stevens-Johnson syndrome(serious disorder of the skin and mucous membranes. painful red or purplish rash) ⚫ Liver damage, cataracts * Use of Allopurinol: • In Chronic gout , in which reabsorption of tophi is more rapid than with uricosuric agents. • When probenecid or sulfinpyrazone cannot be used because of Adverse effects or allergic reactions or when they are providing less than optimal therapeutic effect • For recurrent renal stones • In patients with renal functional impairment 34