Pathophysiology
Gout is a common and complex form of |
arthritis |
Characterization of Gout |
sudden, severe attacks of pain, swelling, redness and tenderness in one or more joints, most often in the big toe |
How Uric Acid normally is eliminated in the body |
dissolves in the blood and passes through the kidneys into the urine. If too much is produced, the kidneys excrete too little uric acid, which it then bbuilds up. |
Build up of Uric Acid characterization |
forming sharp, needlelike uric acid crystals in a joint or surrounding tissue that cause pain, inflammation and swelling |
Nucleic Acid components |
Sugar, phosphate, nitrogenous base |
Nucleotides |
Monomers: phosphate, base, ribose |
Purines |
Guanine and Adenine |
Purine Ring Structure |
double ring structure |
Pyrimadine |
Cytosine, Thymine, Uracil |
Pyrimadine Ring Structure |
single ring |
Formation of Uric Acid |
purine breakdown |
Purine Foods |
liver, shellfish, alcohol |
Xanthine oxidase |
Enzyme required to produce uric acid by the breakdown of purine nucelotides |
Hypoxanthine is catalyzed by xantine oxidase into |
Xanthine |
Xanthine Oxidase catalyzes |
the breakdown reaction of hypoxanthine and xanthine into uric acid |
AMP get converted to |
hypoxanthine |
GMP is converted into |
Xanthine |
Hypoxanthine |
1 oxygen atom |
Xanthine |
2 oxygen |
Uric acid |
3 oxygens |
Xanthine is catalyzed by xanthine oxidase itno |
uric acid |
Uric Acid Pka |
5.3, weak organic acid |
Uric Acid pH |
7.4 (virtually all uric acid is in its DE-protonated and much more soluble urate form |
Function of Xanthine Oxidase |
Uric acid Synthesis |
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Uric Acid Lowering Therapies
Inhibition of Xanthine Oxidase |
Reduces UA generation |
Inhibition of URA1 and GLU9 |
Reduce UA reabsorption in kidney |
Adding Uricase |
Convert UA to Allantoin |
First line Urate lowering therapy |
Xanthine Oxidase Inhibitors |
Second line |
Benzbromarone, Probenecid, pegloticase |
Benzbromarone |
Increase renal urate excretion |
Probenecid |
Increase renal urate excretion |
Pegloticase |
UA degradation |
Purine like XOI |
Allopurinol |
Non-Purine (specific) like XOI |
Febuxostat |
Xanthine Oxidase enzyme |
protein is large, Mol Weight 270 kDa |
active sites of Xanthine Oxidase. |
molybdenum atoms are contained as molybdopterin cofactors |
Allopurinol metabolite |
Oxypurinol. Analogues of hypoxanthine and xanthine. |
Molybdopterins |
class of cofactors found in most molybdenum-containing and all tungsten-containing enzymes |
Synonyms for molybdopterin are: |
MPT and pyranopterin-dithiolate. |
suicide inhibitor of XO |
oxipurinol |
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Uric Acid Reabsorption Inhibitor
major urate reabsorption transporter |
Urate anion transporter 1 URAT1 (SLC22A12 gene) |
Location of Uric Acid Reabsorption Inhibition |
Proximal Convoluted Tubule (PCT) |
Uric Acid Reabsorption Inhibition |
Inhibit URAT1 and GLUT9 |
URAT1 |
OAT transporter family. Anion exchanger that specifically reabsorbs uric acid fro mthe PCT in exchange for Cl |
GLUT9 |
glucose transporter family. proximal tubule of kidney, transports uric acid across basolacteral membrane into the blood |
GLUT9a vs GLUT9b |
differs at N-terminal domain |
Probenecid |
acts by inhibiting URAT 1 and GLUT 9 transporters |
Prototypical uricosuric drug |
probenecid |
Benzobromarone |
Potent uricosuric. More potent than probenecid. |
Uricases
Uricase |
the enzyme responsible for the breaking down of urate to the more water-soluble allantoin was somehow lost during the evolution of man. |
Pegloticase |
porcine recombinant polyethylene-glucol conjugated uricase |
Pegloticase MOA |
genetically altered variant of Escherichia coli, catalyzing uric acid to the water-soluble purine metabolite allantoin |
Uric acid is ____ to allantoin |
Oxidized |
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