Pharmacotherapy of gout, osteoarthritis and rheumatoid arthritis

  • View
    2.906

  • Download
    2

Embed Size (px)

DESCRIPTION

Pharmacotherapy of Gout, Osteoarthritis and Rheumatoid arthritis. ดร.ภก. ศราวุฒิ อู่พุฒินันท์ ภ.บ., วท.ม.(เภสัชกรรมคลินิก), Ph.D. (Pharmaceutical biology) ภาควิชาเภสชักรรมปฏบิตั คณะเภสัชศาสตร์ มหาวิทยาลัยนเรศวร, http://www.pharmyaring.com/pic/p_120512111832.pdf

Text of Pharmacotherapy of gout, osteoarthritis and rheumatoid arthritis

Microsoft Word - Gout_OA_RA_PT3_Sarawut_1July2552.doc

3 (151531), 1 ..2552

1

(Pharmacotherapy of Gout, Osteoarthritis and Rheumatoid arthritis)

.. .., ..(), Ph.D. (Pharmaceutical biology)

1.

(gout), (Osteoarthritis, OA) (Rheumatoid arthritis, RA) 2. gout,

OA RA 3. NSAIDs, colchicine methotrexate

(Gout and Hyperuricemia) (hyperuricemia) (serum uric acid, SUA) 7.0 ./. (gout) (1) hyperuricemia recurrent attacks monosodium urate (MSU) leukocytes synovial fluid, monosodium urate (tophi ), interstitial renal disease uric acid nephrolithiasis

hyperuricemia purine precursors uric acid uric acid Hyperuricemia hyperuricemia

3 (151531), 1 ..2552

2

(S.D.) hyperuricemia (supersaturated concentration) 7.0 mg/dL (416 mmol/mL) 7.5 mg/dL 1 SUA 9.0 mg/dL (0.54 mmol/L) 0.8% 4.5% SUA 9.0-10.0 mg/dL(2)

1 (prior urate levels) monosodium urate cartilage uric acid calculi (nephrolithiasis) (3)

() , serum creatinine, blood urea nitrogen, , ,

6.8 mg/dL (3.6-8.5 mg/dL) 6.0 mg/dL (2.3-6.6 mg/dL)

20-35 100,000 1.6-13.6 1,000 UK 2.6 1,000 10% secondary manifestation diuretics

3 (151531), 1 ..2552

3

10

5%

hyperuricemia hyperuricemia (3, 4)

hyperuricemia synovial fluid end product purines

1,200 mg 600 mg (3) hyperuricemia urate overproduction (10%) underexcretion (90%) (5) (1) 1. 2.

2.1 2.1.1

1. phosphoribosyl pyrophosphate synthetase 2. hypoxanthine guanine phosphoribosyl transferase 3. glucose-6-phosphatase 4. fructose, nicotinic acid, warfarin

2.1.2 1. myeloproliferative disease, polycytemia vera,

hemoglobinopathy, hemolytic anemia, pernicious anemia 2. carcinoma, sarcoma, lymphoma, leukemia, multiple

myeloma 3. (hypoxemia)

3 (151531), 1 ..2552

4

4. fructose, ethanol, cytotoxic drugs 5. sarcoidosis, psoriasis

2.2 1. (dehydration) 2. (acidosis) lactic acidosis, ketoacidosis 3. Bartters syndrome, polycystic kidney, lead

nephropathy, pre-eclampsia 4. hyperparathyroidism,

hypothyroidism, 5. , , pyrazinamide, ethambutol,

nicotinic acid 6. Dawns syndrome, Pagets disease, cystinuria

Overproduction of uric acid (3) Purines uric acid 3 dietary purine, tissue

nucleic acid purine necleotides (salvage pathways) de novo purine bases Purines 3 nucleic acid uric acid ( 2)

uric acid 600-800 mg purine metabolism

uric acid tissue nucleic acids myeloproliferative lymphoproliferative disorders radiotherapy chemotherapy leukemias lymphomas hyperuricemia uric acid nephropathy leukemia allopurinol 3 hyperuricemia urate nephropathy (4)

purines hyperuricemia purine

2 ( 2 ) phophoribosyl pyrophosphate (PRPP) synthetase PRPP PRPP purine hypoxanthine-gaunine phosphoribosyl transferase (HGPRTase)

3 (151531), 1 ..2552

5

HGPRTase guanylic acid guanine hypoxanthine inosinic acid PRPP cosubstrate nucleic acids HGPRTase guanine hypoxanthine uric acid PRPP glutamine purine

2 Purine metabolism(3)

HGPRTase childhood Lesch-Nyhan syndrome choreoathetosis, spasticity, mental retardation, hyperuricemia

uric acid turnover necleoproteins ( type I glycogen storage disease, neoplastic diseases myeloproliferative disorders), purines uric acid enzyme mutation defects ( Lesch-Nyhan syndrome) Underexcretion of uric acid(3)

2 2 3

3 (151531), 1 ..2552

6

hyperuricemia sodium urate glomerulus 4 glomerular filtration, tubular reabsorption, tubular secretion postsecretory reabsorption (5)

90% renal urate-anion exchanger URAT1 apical brush border proximal nephron .. 2002 URAT1 urate anion ( 3 ) urate ( anion ) URAT1 aromatic organic anions nicotinate pyrazinoate ( metabolite pyrazinamide, PZA), lactate, -hydroxybutyrate, acetoacetate inorganic anions chloride nitrate (uricosuric drugs) probenecid, benzbromarone, sulfinpyrazole losartan URAT1 apical side cis-inhibition of URAT1 (antiuricosuric substances) pyrazinoate, nicotinate lactate anion urate anion urate reabsorption trans-stimulation of URAT1 (5)

3 urate . URAT1 = urate transporter-1; OAT = organic anion transporter; MRP4 = ATP-driven efflux pathway; OATV1=volatage-driven organic anion transporter-1; FEu = renal clearance of urate/glomerular filtration rate

URAT1 hyperuricemia -hydroxybutyrate acetoacetate diabetic ketoacidosis, lactic acid , nicotinate pyrazinoate niacin

3 (151531), 1 ..2552

7

pyrazinamide urate , angiotensin II, insulin parathyroid hormone (5)

proximal tubular sodium reabsorption uric acid reabsorption sodium reabsorption ( dehydration) uric acid reabsorption anion Na+ anion cotransporter anion trans-stimulation URAT1 secondary sodium dependency of urate reabsorption urate sodium anion (5)

tubular secretion active transport Postsecretory reabsorption hyperuricemia hyperuricemia

uric acid clearance 1 2

1 Conditions associated with hyperuricemia

Primary gout Obesity Diabetic ketoacidosis Sarcoidosis Myeloproliferaive disorders Congestive heart

failure Lactic acidosis Renal dysfunction Lypmphoproliferative disorders Down syndrome Starvation Lead toxicity Chronic hemolytic anemia Hyperparathyroidism Toxemia of pregnancy Acute alcoholism Pernicious anemia Hypoparathyroidism Glycogen storage disease type 1

Acromegaly

Psoriasis Hypothyroidism

3 (151531), 1 ..2552

8

2 (5) Urate-increasing agents Implicated Mechanisms

Pyrazinamide, Nicotinate, Lactate, -hydroxybutyrate, acetoacetate

Trans-stimulation of URAT1

Salicylate (low dose, 1-2g/day) (2), Ethambutol

renal urate excretion

Diuretics renal tubular reabsorption associated with volume depletion, may stimulate URAT1

Cyclosporin renal tubular reabsorption associated with GFR, hypertension, interstitial nephropathy

Tacrolimus Similar to cyclosporin -blockers Unknown (no change in renal urate excretion) Drug-induced gout or hyperuricemia (4)

hyperuricemia 2 cytotoxic drugs levodopa hyperuricemia gout thiazide ( vasodilator ) allopurinol

hyperuricemia cyclosporin 24 cyclosporin 2 omeprazole

hyperuricemia purine 3-5 24 600-800 mg 600 mg 600 mg 600 mg 24 purine 1,000 mg 24 1,000 mg

physical stress

3 (151531), 1 ..2552

9

(1)

1.

(dehydration) (metabolic acidosis) pyrazinamide ethambutol

1-2

2.

1

1 ()

24 .. 800 ./24 .. 13.0 ./. 10.0 ./. 1,100 . ()

3 phagocytes 2 1) opsonized (phagocytosed) phagocyte lysosomal fusion, respiratory burst 2) lipid membranes cross-linking glycoproteins phagocytes

3 (151531), 1 ..2552

10

interleukin (IL)-8 monocytic cells neutrophils (5)

3

. (5) ApoB = apolipoprotein B; ApoE = apolipoprotein E; C1q, C3a,C3b, C5a, C5b-9 = complement membrane attack complex; IL = interleukin; LDL = low-density lipoprotein; LTB4 = leukotriene B4; MCP-1 = monocyte chemoattractant protein-1/CCL2; MIP-1 macrophage inflammatory protein-1/CCL3; MMP-3 = matrix metalloproteinase-3; NO = nitrous oxide; PAF = platelet-activating factor; PGE2 = prostaglandin E2; PLA2 = phospholipase A2; PPAR- = peroxisome proliferator-activated receptor- ligand; PPAR = peroxisome proliferator-activated receptor- ligand; TGF- = transcription growth factor-; TNF- = tumor necrosis factor-; S100A8/A9 = myeloid-related protein; sTNFr = soluble tumor necrosis factor receptor.

complements

(synovial lining cells) monocytes mast cells neutrophils neutrophils phagocytes macrophages (M) M (less differentiated cells) TNF- (endothelial cells) M (well-differentiated cells) TNF- endothelial cells Monocytes TNF-, IL-1, IL-6, IL-8 cyclooxygenase-2 (COX-2) monocytes

3 (151531), 1 ..2552

11

mast cells histamine C3a, C5a IL-1 , vascular permeability kinins, complement cleavage peptides vasoactive prostaglandins (5)

neutrophils (Neutrophil influx) IL-1, TNF-, chemokines IL-8 MCP-1 neutrophils endothelial cells (clustering) E-selectin endothelial cells cytokine IL-1 TNF- Colchicine selectins neutrophils neutrophils C5a, LTB4, PAF, IL-1 IL-8 IL-8 growth-related gene chemokines IL-8 90% monocytes neutrophils (5)

neutrophils (apoptosis) Differentiated macrophage macrophage leukocytes endothelial cells TGF- IL-1 IL-10 PPAR- monocytes neutrophil macrophage (5)

, desensitization receptors chemokines, lipoxins, IL-1 receptor antagonist Vascular permeability Apo B E

cytokines, chemokines, proteases oxidants (chronic synovitis), (cartilage loss) (bone erosion) leukocytes (tophi) (chondrolysis) hyp