Allopurinol

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Lecture on GOUT

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Allopurinol

  1. 1. Allopurinol Prof. Dr. Shah Murad [email_address]
  2. 2. ZYLOPRIM (allopurinol)
  3. 3. <ul><li>ZYLOPRIM is known chemically as 1,5-dihydro-4 H -pyrazolo [3,4- d ]pyrimidin-4-one. </li></ul><ul><li>It is a xanthine oxidase inhibitor which is administered orally. </li></ul>
  4. 4. <ul><li>Xanthine oxidase is an enzyme that catalyzes the oxidation of hypoxanthine to xanthine and can further catalyze the oxidation of xanthine to uric acid . </li></ul><ul><li>This enzyme plays an important role in the catabolism of purines in some species, including human </li></ul>
  5. 5. <ul><li>Xanthine oxidase can be converted to xanthine dehydrogenase by reversible sulfhydryl oxidation </li></ul>
  6. 6. Reaction <ul><li>The following chemical reactions are catalyzed by xanthine oxidase: </li></ul><ul><li>hypoxanthine + H2O + O2>>>>xanthine+ H2O2 </li></ul><ul><li>xanthine + H2O + O2 >>>> uric acid + H2O2 </li></ul>
  7. 7. Hypoxanthine Xanthine
  8. 8. Protein structure <ul><li>The protein is large, having a molecular weight of 270,000, and has 2 flavin molecules (bound as FAD), 2 molybdenum atoms, and 8 iron atoms bound per enzymatic unit. </li></ul><ul><li>The molybdenum atoms are contained as molybdopterin cofactors and are the active sites of the enzyme. </li></ul><ul><li>The iron atoms are part of [2Fe-2S] ferredoxin iron-sulfur clusters and participate in electron transfer reactions </li></ul>
  9. 9. Catalytic mechanism <ul><li>The active site of XO is composed of a molybdopterin unit with the molybdenum atom also coordinated by terminal oxygen ( oxo ), sulfur atoms and a terminal hydroxide . </li></ul><ul><li>In the reaction with xanthine to form uric acid, an oxygen atom is transferred from molybdenum to xanthine. </li></ul><ul><li>The reformation of the active molybdenum center occurs by the addition of water. </li></ul><ul><li>Like other known molybdenum-containing oxidoreductases, the oxygen atom introduced to the substrate by XO originates from water rather than from dioxygen (O2) </li></ul>
  10. 10. Clinical significance <ul><li>In humans, xanthine oxidase is normally found in the liver and not free in the blood. </li></ul><ul><li>During severe liver damage, xanthine oxidase is released into the blood, so a blood assay for XO is a way to determine if liver damage has happened </li></ul>
  11. 11. <ul><li>As well, because xanthine oxidase is a metabolic pathway for uric acid formation, the xanthine oxidase inhibitor allopurinol is used in the treatment of gout . </li></ul><ul><li>Since xanthine oxidase is involved in the metabolism of 6-mercaptopurine , caution should be taken before administering allopurinol and 6-mercaptopurine, or its prodrug azathioprine , in conjunction. </li></ul>
  12. 12. <ul><li>Xanthinuria is a rare genetic disorder where the lack of xanthine oxidase leads to high concentration of xanthine in blood and can cause health problems such as renal failure . </li></ul><ul><li>There is no specific treatment, sufferers are advised by doctors to avoid foods high in purine and to maintain a high fluid intake. </li></ul>
  13. 13. Inhibitors <ul><li>Xanthine oxidase inhibitor </li></ul><ul><li>Inhibitors of XO include allopurinol , oxypurinol ,and phytic acid </li></ul>
  14. 14. <ul><li>Allopurinol is taken in tablet form (oral). </li></ul><ul><li>It is taken in low dosages at first. </li></ul><ul><li>The dosage is gradually increased to control uric acid levels. </li></ul>
  15. 15. MOA <ul><li>Allopurinol prevents the release of a substance called xanthine oxidase, which helps in the formation of uric acid. </li></ul><ul><li>In treatment for gout , allopurinol blocks the production of uric acid in the body. </li></ul>
  16. 16. <ul><li>Allopurinol may be prescribed to prevent gout attacks. It also may be used because of: </li></ul><ul><li>Overproduction of uric acid. </li></ul><ul><li>Frequent gout attacks. </li></ul><ul><li>Presence of gritty, chalklike clumps of uric acid crystals ( tophi ). </li></ul><ul><li>Failure of other medicines to adequately reduce uric acid levels. </li></ul><ul><li>Allergy to uricosuric medications, which increase the elimination of uric acid, or serious side effects from these medicines. Uricosuric medications include probenecid (Probalan) and sulfinpyrazone (Anturane). </li></ul><ul><li>Poor kidney function. </li></ul><ul><li>History of uric acid kidney stones. </li></ul>
  17. 17. <ul><li>Allopurinol may also be used for the prevention of kidney disease in people going through treatment for cancer. </li></ul><ul><li>The dose of allopurinol may need to be lower for people who have chronic kidney disease or are taking azathioprine. </li></ul>
  18. 18. Allopurinol is not recommended for people who <ul><li>Have a known sensitivity to allopurinol. </li></ul><ul><li>Have a condition in which there is too much iron in the body ( hemochromatosis ). </li></ul><ul><li>Allopurinol should not be started for the first time by people who are still having symptoms caused by a gout attack. </li></ul>
  19. 19. <ul><li>Allopurinol lowers the amount of uric acid in the body. </li></ul><ul><li>After the proper dose is reached, the uric acid levels should return to normal. </li></ul><ul><li>doctor will monitor uric acid level within one month of starting or changing a dose of allopurinol. </li></ul><ul><li>Treatment with allopurinol can reduce the size of tophi . </li></ul>
  20. 20. Side Effects <ul><li>Skin rash is a common side effect. </li></ul><ul><li>Because a skin rash may be a symptom of an allergic reaction to allopurinol, have your doctor evaluate any skin rash that develops while you are taking this medicine. </li></ul>
  21. 21. Rare, serious side effects include <ul><li>Inflammation of the liver ( hepatitis ). </li></ul><ul><li>Failure of bone marrow to produce blood cells ( aplastic anemia ). </li></ul><ul><li>Inflammation of blood vessels ( vasculitis ). </li></ul><ul><li>Allopurinol hypersensitivity syndrome (a widespread rash, fever, mouth sores, poor kidney function, liver inflammation, and other complications), which can be life-threatening . </li></ul>
  22. 22. <ul><li>Allopurinol interferes with many other medicines. </li></ul><ul><li>It may increase or decrease the levels of other medicines, which may increase the toxicity of these medicines or reduce their effectiveness. </li></ul>
  23. 23. <ul><li>Allopurinol should not be used until the symptoms of a gout attack are gone. But if you are already taking allopurinol, continue to take it (even during an attack). </li></ul><ul><li>Gout attacks may increase at first for some people taking allopurinol. </li></ul><ul><li>To avoid this, doctors may prescribe either colchicine, which blocks the inflammation caused by uric acid crystals, or low-dose nonsteroidal anti-inflammatory drugs ( NSAIDs ) to be taken at the same time. </li></ul><ul><li>After normal uric acid levels have been maintained for 6 to 12 months and no further attacks occur, colchicine or NSAIDs do not need to be taken. </li></ul><ul><li>Because of the rare risk of serious side effects, many doctors may prefer uricosuric medications to allopurinol. </li></ul>
  24. 24. <ul><li>Laboratory studies, including a complete blood count (CBC) and liver and kidney function studies, may be done after a few months of using allopurinol. </li></ul>
  25. 25. NSAIDs <ul><li>INDOCIN is a non-steroidal anti-inflammatory drug (NSAID) that exhibits antipyretic and analgesic properties. </li></ul>
  26. 26. MOA <ul><li>INDOCIN is a potent inhibitor of prostaglandin synthesis . </li></ul><ul><li>Prostaglandins sensitize afferent nerves and potentiate the action of bradykinin in inducing pain in animal models. </li></ul><ul><li>prostaglandins are known to be among the mediators of inflammation. </li></ul><ul><li>Since indomethacin is an inhibitor of prostaglandin synthesis, its mode of action may be due to a decrease of prostaglandins in peripheral tissues. </li></ul>
  27. 27. Other uses <ul><li>INDOCIN has been shown to be an effective anti-inflammatory agent, appropriate for long-term use in rheumatoid arthritis , ankylosing spondylitis , and osteoarthritis . </li></ul><ul><li>INDOCIN affords relief of symptoms; it does not alter the progressive course of the underlying disease. </li></ul>
  28. 28. <ul><li>INDOCIN suppresses inflammation in rheumatoid arthritis as demonstrated by relief of pain, and reduction of fever, swelling and tenderness. </li></ul><ul><li>Improvement in patients treated with INDOCIN for rheumatoid arthritis has been demonstrated by a reduction in joint swelling, average number of joints involved, and morning stiffness; by increased mobility as demonstrated by a decrease in walking time; and by improved functional capability as demonstrated by an increase in grip strength. </li></ul><ul><li>INDOCIN may enable the reduction of steroid dosage in patients receiving steroids for the more severe forms of rheumatoid arthritis. </li></ul><ul><li>In such instances the steroid dosage should be reduced slowly and the patients followed very closely for any possible adverse effects. </li></ul>
  29. 29. <ul><li>Capsules INDOCIN have been found effective in relieving the pain, reducing the fever, swelling, redness, and tenderness of acute gouty arthritis </li></ul>
  30. 30. PK <ul><li>Following single oral doses of Capsules INDOCIN 25 mg or 50 mg, indomethacin is readily absorbed, attaining peak plasma concentrations of about 1 and 2 mcg/mL, respectively, at about 2 hours. </li></ul><ul><li>Orally administered Capsules INDOCIN are virtually 100% bioavailable, with 90% of the dose absorbed within 4 hours. </li></ul><ul><li>A single 50 mg dose of Oral Suspension INDOCIN was found to be bioequivalent to a 50 mg INDOCIN capsule when each was administered with food </li></ul>
  31. 31. <ul><li>Indomethacin is eliminated via renal excretion, metabolism , and biliary excretion. </li></ul><ul><li>Indomethacin undergoes appreciable enterohepatic circulation . </li></ul><ul><li>The mean half-life of indomethacin is estimated to be about 4.5 hours. </li></ul><ul><li>With a typical therapeutic regimen of 25 or 50 mg t.i.d. , the steady-state plasma concentrations of indomethacin are an average 1.4 times those following the first dose </li></ul>
  32. 32. <ul><li>The rate of absorption is more rapid from the rectal suppository than from Capsules INDOCIN. </li></ul><ul><li>Ordinarily, therefore, the total amount absorbed from the suppository would be expected to be at least equivalent to the capsule. </li></ul>
  33. 33. <ul><li>Indomethacin exists in the plasma as the parent drug and its desmethyl, desbenzoyl, and desmethyl-desbenzoyl metabolites, all in the unconjugated form. </li></ul><ul><li>About 60 percent of an oral dosage is recovered in urine as drug and metabolites (26 percent as indomethacin and its glucuronide), and 33 percent is recovered in feces (1.5 percent as indomethacin). </li></ul>
  34. 34. <ul><li>About 99% of indomethacin is bound to protein in plasma over the expected range of therapeutic plasma concentrations. </li></ul><ul><li>Indomethacin has been found to cross the blood-brain barrier and the placenta . </li></ul>
  35. 35. Probenecid (Benuryl) <ul><li>is a uricosuric drug that increases uric acid excretion in the urine . </li></ul><ul><li>It is primarily used in treating gout and hyperuricemia . </li></ul><ul><li>Probenecid competitively inhibits the renal excretion of some drugs, thereby increasing their plasma concentration and prolonging their effects. </li></ul>
  36. 36. <ul><li>In the kidneys probenecid is filtered at the glomerulus , secreted in the proximal tubule and reabsorbed in the distal tubule . </li></ul><ul><li>Probenecid's exact mechanism is explained as follows. The kidney's organic anion transporter (OAT) reclaims uric acid from the urine and returns it to the plasma. Probenecid interferes with these systems. </li></ul><ul><li>If probenecid (an organic acid) is administered to a patient, the OAT binds to probenecid instead of to uric acid, preventing the reabsorption of uric acid. </li></ul><ul><li>As a result, more uric acid leaves the body in the urine, lowering the uric acid concentration in the plasma . </li></ul>
  37. 37. Uses <ul><li>probenecid was shown to more than double blood concentrations of oseltamivir (trade name Tamiflu), an antiviral drug used to combat influenza . </li></ul><ul><li>This is significant because nations are currently stockpiling oseltamivir in anticipation of an influenza pandemic , and there could be supply shortages. </li></ul><ul><li>During World War II, probenecid was used to extend limited supplies of penicillin , and is still currently used to increase antibiotic concentrations in serious infections. </li></ul><ul><li>It has also found use as a masking agent </li></ul>
  38. 38. CORTICOSTEROIDS <ul><li>corticosteroids are naturally produced by your own body and may help reduce swelling, redness and pain in joints. </li></ul><ul><li>Systemic corticosteroids come in a pill form or as an injection </li></ul>
  39. 39. <ul><li>There is inconclusive evidence for the efficacy and effectiveness of systemic corticosteroids in the treatment of acute gout. </li></ul><ul><li>Patients with gout did not report serious adverse effects from systemic corticosteroids, when used for short term. </li></ul>
  40. 40. USES of corticosteroids <ul><li>Gout attacks that are limited to a single joint. </li></ul><ul><li>Gout attacks that do not respond to nonsteroidal anti-inflammatory drugs ( NSAIDs ) or colchicine. </li></ul><ul><li>People who cannot take NSAIDs or colchicine, such as those with kidney disease or a history of serious ulcer disease and gastrointestinal bleeding. </li></ul><ul><li>Corticosteroids may also be used by people who have congestive heart failure or take the blood-thinner warfarin, or who are allergic to aspirin. </li></ul>
  41. 41. Side Effects <ul><li>Mood swings. </li></ul><ul><li>Nervousness. </li></ul><ul><li>Insomnia . </li></ul><ul><li>Weight gain. </li></ul><ul><li>Fluid retention. </li></ul><ul><li>Very rounded (moon) face. </li></ul><ul><li>Poor wound healing. </li></ul><ul><li>Increased risk of infection. </li></ul><ul><li>High blood pressure . </li></ul><ul><li>Diabetes . </li></ul>
  42. 42. Uncommon short-term side effects <ul><li>Muscle weakness. </li></ul><ul><li>Glaucoma . </li></ul><ul><li>Stomach ulcers . </li></ul><ul><li>Acne . </li></ul><ul><li>Long-term side effects include </li></ul><ul><li>Osteoporosis . </li></ul><ul><li>Cataracts (uncommon). </li></ul><ul><li>Damage to the hip, shoulder, or knee joints (uncommon). </li></ul>
  43. 43. ACTH <ul><li>Corticotropin alone or in combination with colchicine is more rapidly effective and associated with fewer adverse effects than indomethacin. </li></ul><ul><li>This regimen may be considered an alternative, especially for patients with medical problems in which other regimens are contraindicated. </li></ul>
  44. 44. <ul><li>adrenocorticotropic hormone (ACTH) possess potent antirheumatic properties. </li></ul><ul><li>rheumatoid arthritis, </li></ul><ul><li>rheumatoid (ankylosing) spondylitis, </li></ul><ul><li>acute rheumatic fever, </li></ul><ul><li>disseminated lupus erythematosus, </li></ul><ul><li>periarteritis nodosa, </li></ul><ul><li>psoriatic arthritis, </li></ul><ul><li>dermatomyositis, and </li></ul><ul><li>gout </li></ul>
  45. 45. <ul><li>In general the effects of ACTH/Cortisone are temporary and they cause suppression rather than cure of the disease processes. </li></ul><ul><li>Improvement is maintained usually only by continuing administration, and on hormonal withdrawal prompt or fairly prompt relapse of the disease manifestations ensues </li></ul>
  46. 46. ACTH <ul><li>Its chief function is to stimulate the cortex of the adrenal gland to secrete adrenocortical steroids, chief among them cortisone . </li></ul><ul><li>The release of adrenocorticotropic hormone (ACTH), also known as corticotropin, is stimulated by corticotropin-releasing factor (CRF), a secretion of the hypothalamus. </li></ul>
  47. 47. <ul><li>ACTH secretion is an excellent example of the regulation of a biological system by a negative-feedback mechanism; high levels of adrenocortical steroids in the blood tend to decrease ACTH release, whereas low steroid levels have the opposite effect. </li></ul>
  48. 48. <ul><li>ACTH has the same pharmacologic and clinical effects as cortisone when given intravenously or intramuscularly; </li></ul><ul><li>however, it has no value when applied externally and cannot be taken orally since it is deactivated by digestive enzymes </li></ul>
  49. 49. ARTHRITIS
  50. 50. <ul><li>Arthritis literally means joint inflammation. Arthritis is not a single disease . </li></ul><ul><li>Arthritis refers to a group of more than 100 rheumatic diseases and other conditions that can cause pain, stiffness and swelling in the joints. </li></ul>
  51. 51. <ul><li>The most common form, osteoarthritis (degenerative joint disease) is a result of trauma to the joint, infection of the joint, or age. Other arthritis forms are rheumatoid arthritis and psoriatic arthritis , autoimmune diseases in which the body attacks itself. </li></ul><ul><li>Septic arthritis is caused by joint infection . Gouty arthritis is caused by deposition of uric acid crystals in the joint, causing inflammation. </li></ul>
  52. 52. <ul><li>Any part of your body can become inflamed or painful from arthritis. Some rheumatic conditions can result in debilitating, even life-threatening complications or may affect other parts of the body including the muscles , bones , and internal organs. </li></ul>
  53. 53. <ul><li>Osteoarthritis </li></ul>Rheumatoid Arthritis
  54. 54. <ul><li>Psoriatic Arthritis </li></ul><ul><li>Fibromyalgia </li></ul><ul><li>Scleroderma </li></ul><ul><li>Lupus / SLE </li></ul>
  55. 55. <ul><li>Extra-articular features of joint disease </li></ul><ul><li>Cutaneous nodules </li></ul><ul><li>Cutaneous vasculitis lesions </li></ul><ul><li>Lymphadenopathy </li></ul><ul><li>Oedema </li></ul><ul><li>Ocular inflammation </li></ul><ul><li>Urethritis </li></ul><ul><li>Tenosynovitis ( tendon sheath effusions ) </li></ul><ul><li>Bursitis (swollen bursa ) </li></ul><ul><li>Diarrhea </li></ul><ul><li>ulceration </li></ul>
  56. 56. <ul><li>Treatment options vary depending on the type of arthritis and include Physical therapy , lifestyle changes (including exercise and weight control), medications and dietary supplements (symptomatic or targeted at the disease process causing the arthritis). </li></ul><ul><li>Arthroplasty (joint replacement surgery) may be required in eroding forms of arthritis. </li></ul>
  57. 57. <ul><li>In general, studies have shown that physical exercising of the affected joint can have noticeable improvement in terms of long-term pain relief. </li></ul><ul><li>Furthermore, exercising of the arthritic joint is encouraged to maintain the health of the particular joint and the overall body of the person </li></ul>

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