Download Pharmacology Ch 48 837-843 Integrative Inflammation

Pharmacology Ch 48 837-843
Integrative Inflammation Pharmacology: Gout
-humans excrete most purines as soluble uric acid; high levels can cause deposition of crystals in
joints, and most frequently in first MTP joint
Physiology of Purine Metabolism – intermediates of purine metabolism are toxic to some cells,
necessitating regulation of synthesis and degradation
-purines are synthesized by 2 pathways: de novo synthesis and salvage pathway
1. De novo synthesis – first step is reaction of phosphoribosyl pyrophosphate (PRPP) with
glutamine
-hydrolysis of pyrophosphate makes this pathway irreversible
-glutamine is precursor for inosine monophosphate, precursor for both purines
-reaction of PRPP with glutamine is catalyzed by amidophosphoribosyltransferase (amidoPRT),
which is activated allosterically by PRPP
-cellular level of PRPP is MOST IMPORTANT DETERMINANT OF PURINE SYNTHESIS
2. Salvage Pathway – catalyzed by enzyme hypoxanthine guanine phosphoribosyltransferase
(HGPRT), which transfers PRPP to hypoxanthine or guanine  forms IMP or GMP
-increased activity of salvage pathway has 2 consequences: scavenging activity DEPLETES PRPP,
and the salvage pathway also leads to generation of more ATP and GTP, which inhibit amidoPRT
do decrease de novo purine synthesis
-degradation of purines occurs in a CONVERGENT mechanism; AMP and GMP  hypoxanthine
 xanthine, which is a product of purine metabolism. Xanthine is a substrate for xanthine
oxidase which converts Xanthine  Uric Acid
-high DE NOVO synthesis is most important generator of purine breakdown products, and high
activity increases purine turnover to result in increased plasma uric acid
-Lesch-Nyhan Syndrome – inherited absence of HGPRT is characterized by self-mutilation,
mental retardation, and hyperuricemia
-uric acid is eliminated by kidney (65%) and GI tract (35%)
-90% of uric acid is reabsorbed through URAT1 expressed in proximal renal tubule
Pathophysiology of Gout – gout correlates strongly with increased plasma uric acid levels, and a
plasma level of 7.0mg/DL for men or 6.0mg/dL for women is classified as hyperuricemia
-any variable that decreases solubility of urate can promote urate crystal deposition
-gout occurs most often at peripheral joints where the temperature is lower (less soluble)
-synovial fluid is more acidic than blood, favoring crystal formation
-pathogenesis of gout reflects deposition of urate crystals in periarticular fibrous tissue of
synovial joints after years of hyperuricemia
Gout occurs in 4 stages:
1. Asymptomatic Hyperuricemia – due to increased synthesis or decreased breakdown of
purines
2. Acute Gout – symptomatic and involves acute arthritic attack of a single joint (usually
MTP, known as podagra)
3. Intercritical Phase – asymptomatic hyperuricemia for long periods of time
4. Chronic Gout – hyperuricemia with development of tophi (uric acid crystals) and
recurrent gout attacks
-Uric acid released from injured and dying cells can function as a danger signal to initiate an
inflammatory response leading to tissue repair
-pathologic urate crystals activate monocytes and synoviocytes by binding to TLRs
-in monocytes, urate crystal binding and phagocytosis initiate assembly of intracellular
protein complex NALP-3 Inflammasome which activates caspase 1, a proteolytic
enzyme that cleaves pro IL-1B to IL-1B, a cytokine that initiates immune responses
including endothelial cell activation and increased neutrophil transmigration
Pharmacology of Gout – two main treatment strategies: management of acute attacks of gouty
arthritis, and management of chronic gout
NSAID treatment of Acute Gout – NSAIDs inhibit COX to inhibit prostaglandin and thromboxane
synthesis to treat inflammatory response to the urate crystals in joint
-indomethacin is one of the NSAIDs used most often to treat acute gout
Colchicine treatment of Acute Gout – colchicine binds to tubulin to inhibit polymerization of
microtubules and inhibits cell division and intracellular trafficking.
-in acutely inflamed joint, colchicine inhibits inflammatory response by inhibiting neutrophil
activation through the following mechanisms:
-decreased trafficking of phagocytosed particles to lysosomes, decreased release of chemotactic
factor, decreased motility and adhesion of neutrophils, and decreased tyrosine phosphorylation
of proteins, resulting in decreased in leukotriene B4 (LTB4) synthesis
-Colchicine inhibits turnover of epithelial cells in GI, diarrhea is common, can be
myelosuppressive, and undergoes heavy enterohepatic recirculation, secreted into bile by
multidrug-resistance (MDR) protein
Glucocorticoids for Acute Gout – powerful anti-inflammatory and immunosuppressive effects
and inhibit inflammatory response during acute attack
-widespread adverse effects cause the use to be reserved for acute polyarticular gout
Management of Chronic Gout:
Agents that Decrease Uric Acid Synthesis
-Allopurinol – drug designed to inhibit uric acid synthesis; it is an analog of Xanthine that inhibits
Xanthine Oxidase to reduce concentration of uric acid in blood
-allopurinol acts as a substrate and gets oxidized to oxypurinol which inhibits xanthine oxidase
by preventing molebdenum in active site of enzyme from interconverting between oxidation
states, therefore it inhbits conversion of hypoxanthine to xanthine and xanthine  uric acid and
increases plasma levels of hypoxanthine and xanthine
-used in treatment of chronic gout, especially in cases of increased purine degradation
-NSAID or colchicine is often co-administered to reduce chance of acute gout attack
Febuxostat – nonpurine small-molecule inhibitor of xanthine oxidase approved for treatment of
chronic gout
Agents that Increase Uric Acid Excretion – called uricosuric agents,
-Probenecid increases urate excretion by targeting URAT1 receptor in renal tubules to treat
chronic hyperuricemia, can cause kidney stone formation
Sulfinpyrazone – uricosuric agent acts same way as probenecid but is more potent and is
effective in mild-moderate renal insufficiency
Benxbromarone – uricosuric agent with similar mechanism to probenecid but is more potent;
however, it can cause hepatotoxicity
Losartan – angiotensin II receptor antagonist that has a modest uricosuric effect, used in
patients with chronic hypertension and gout
Agents that Enhance Uric Acid Metabolism – tumor lysis syndrome can lead to massive renal
injury by releasing uric acid in the blood
-exogenous uricase can be co-administered with chemotherapy to reduce plasma urate
-Rasburicase – recombinant uricase used to treat high levels of plasma urate
-Pegloticase – pegylated formulation of recombinant porcine uricase, approved for treatment of
gout refractory to conventional therapy