Gout_medchem.pdf

CPP426 Drugs used to treat GOUT Dr. Lama Alshabani, BSc. Pharm, MSc, PhD College of Pharmacy Office: 3.306.48 [email protected] Reference Lemke TL, Williams DA. Foye’s Principles of Medicinal Chemistry, Lippincott Williams & Wilkins (Chapter 36) What is Gout?...

CPP426 Drugs used to treat GOUT Dr. Lama Alshabani, BSc. Pharm, MSc, PhD College of Pharmacy Office: 3.306.48 [email protected] Reference Lemke TL, Williams DA. Foye’s Principles of Medicinal Chemistry, Lippincott Williams & Wilkins (Chapter 36) What is Gout? Gout is an inflammatory disease characterized by elevated levels of uric acid (as urate ion) in the plasma and urine Two forms, acute and chronic. Acute gouty arthritis: results from the accumulation of needle-like crystals of monosodium urate monohydrate within the joints, synovial fluid, and periarticular tissue and usually appears without warning. Initiating factors may be minor trauma, fatigue, emotional stress, infection, overindulgence in alcohol or food, or drugs, such as penicillin or insulin. What is Gout? Chronic gout symptoms develop as permanent erosive joint deformity appears. The high levels of extracellular urate may result from: 1- increased uric acid biosynthesis 2- decreased urinary excretion of uric acid 3- or perhaps, a combination of both.  Uric Acid Formation Formation of uric acid from adenine and guanine Xanthine is a metabolic product of adenine and guanine (De-amination step) Uric acid is formed by the oxidation of xanthine by the enzyme xanthine oxidase. Thus, uric acid is the excretory product of purine metabolism in humans  Normal pool levels of uric acid are approximately 1,000 to 1,200 mg in males and half that in females. In patients suffering from gout, these levels may be as high as two- or three times the normal levels. Uric acid is a weak acid with two pk, values 5.7 and 10.3, with very low water solubility (~6 mg/100 mL). Blood levels of urate are maintained by a careful balance between its formation and excretion. The kidney plays a dominant role in urate elimination, excreting about 70% of the daily urate production. The excretion of urate has been implicated in the development of hyperuricemia that leads to gout.  At physiological pH, uric acid exists primarily as the monosodium salt, which is approximately 50 times more soluble in aqueous media than the free acid When the levels of Uric acid become High.. The solubility limits of sodium urate are exceeded, and precipitation of the salt from the resulting supersaturated solution causes deposits of urate crystals to form. It is the formation of these urate crystals in joints and connective tissue that initiate attacks of gouty arthritis.  In humans, the excretion of urate requires the urate anion transporter (URAT1) located in renal proximal tubule cells, which plays a central role in urate homeostasis. The URAT1 is targeted by uricosuric (urate lowering agents) and anti-uricosuric agents that affect urate excretion.  Therapeutic Approach The control of gout has been approached from the following therapeutic strategies: 1) Control of acute attacks by drugs that reduce inflammation caused by the deposition of urate crystals (these drugs may possess only an anti-inflammatory component, such as colchicine, or both anti-inflammatory and analgetic actions, such as indomethacin, phenylbutazone and naproxen) 2) Increasing the rate of uric acid excretion "uricosuric drugs" and include probenecid and sulfinpyrazone 3) Inhibiting the biosynthesis of uric acid by inhibiting the enzyme xanthine oxidase (allopurinol) Acute Gout Treatment of acute gout includes NSAIDs, such as indomethacin, colchicine, and glucocorticoids. The choice of an NSAID generally is based on the side effect profile. Colchicine: Pale-yellow powder that is obtained from various species of Colchicum. pKa 12.4, used in gout treatment from 6th century AD Colchicine does not alter serum levels of uric acid – it only retard the inflammation caused by…(what?)  Colchicine inhibits the production of lactic acid, causing an increase in the pH of synovial tissue and, thus, a decrease in urate deposition, because uric acid is more soluble at the higher pH. Colchicine inhibits the release of lysosomal enzymes during phagocytosis that also contributes to the reduction of inflammation. Because colchicine does not lower serum urate levels, it has been found to be beneficial to combine colchicine with a uricosuric agent, particularly probenecid. Colchicine metabolized mainly in the liver, with the major metabolite being the amine through amide hydrolysis. Chronic Gout A) Drugs That Increase Uric Acid Secretion (PROBENECID and SULFINPYRAZONE) B) Drugs That Decrease Uric Acid Formation (ALLOPURINOL)  A) Drugs That Increase Uric Acid Secretion PROBENECID Probenecid promotes the excretion of uric acid by: 1. Inhibiting the urate anion exchange transporter (URAT1) 2. Decreasing the reabsorption of uric acid in the proximal tubules. The overall effect is to decrease plasma uric acid concentrations, thereby decreasing the rate and extent of urate crystal deposition in joints and synovial fluids. Probenecid is derived from the series of N-dialkylsulfamyl benzoates Uricosuric activity of these compounds increases with increasing size of the alkyl group in the series methyl, ethyl, and propyl.  It is extensively metabolized, with only 5 to 10% being excreted as unchanged drug. The major metabolites detected result from: 1. glucuronide conjugation of the carboxylic acid 2. oxidation of the n-propyl side chain and subsequent oxidation of the resulting alcohol to the carboxylic acid derivative 3. oxidation of the n-propyl group 4. N-dealkylation. Those metabolites possessing a free carboxylic acid function generally possess some uricosuric activity.  Probenecid is indicated for the treatment of hyperuricemia associated with gouty arthritis Treatment should not begin until an acute attack has subsided. It is not recommended in individuals with known uric acid kidney stones or blood dyscrasias (imbalance) or for children under 2 years of age. A) Drugs That Increase Uric Acid Secretion SULFINPYRAZONE Sulfinpyrazone produces its uricosuric effect in a manner similar to that of probenecid. Its synthesis is similar to that of phenylbutazone It also possesses, not surprisingly, some of the properties of phenylbutazone (an inhibitor of human platelet prostaglandin synthesis) resulting in a decrease in platelet release and a reduction in platelet aggregation.  Sulfinpyrazone is a strong acid (pKa = 2.8), a factor that is important in the production of the uricosuric effect, because: the stronger the acid, the more potent the uricosuric effect. Polar substitution on the side chain also influences uricosuric activity The metabolites produced result from sulfoxide reduction, sulfur and aromatic oxidation, and C-glucuronidation of the heterocyclic. The metabolite resulting from p-hydroxylation of the aromatic ring possesses uricosuric effects Sulfinpyrazone is indicated for the treatment of chronic and intermittent gouty arthritis.  B) Drugs That Decrease Uric Acid Formation ALLOPURINOL Allopurinol originally was designed as an antineoplastic antimetabolite to antagonize the actions of key purines, and it differs from normal purines only by the inversion of the nitrogen and carbon atoms at the 7- and 8-positions of the purine ring system but was found to have little or no effect on experimental tissues. It was subsequently found that allopurinol serves as a substrate for xanthine oxidase and reversibly inhibits that enzyme. Normally, uric acid is a major metabolic end product in humans. When allopurinol is administered, however, xanthine and hypoxanthine are elevated in the urine, and uric acid levels decrease.  When the synthesis of uric acid is inhibited  plasma urate levels decrease (supersaturated solutions of urate are no longer present, and urate crystal deposits dissolve)  eliminating the primary cause of gout. The increased plasma levels of hypoxanthine and xanthine pose no real problem, because they are more soluble than uric acid and are readily excreted. Allopurinol is rapidly metabolized via oxidation with the major oxidation metabolite, alloxanthine (oxypurinol). Allopurinol is indicated for the treatment of primary and secondary gout, for malignancies such as leukemia and lymphoma. End of lecture Thank you