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Slide 1: Nonsteroidal Anti-inflammatory Drugs, DiseaseModifying Antirheumatic Drugs, Nonopioid Analgesics, & Drugs Used in Gout Florencia D. Munsayac, MD, MBA, RMT
Slide 2: The Inflammatory Response 3 Phases of Inflammation: - Acute Inflammation/acute phase - The Immune Response/sub-acute or delayed phase Chronic Inflammation/chronic proliferative phase -
Slide 3: Some of the mediators of acute inflammation & their effects Mediators Histamine Serotonin Bradykinin Prostaglandins Vasodilation Vascular Permeability Chemotaxis Pain ++ +/+++ +++ - +++ +++ +++ + - Leukotrienes
Slide 4: Some of the Mediators of Chronic Inflammation Mediators Interleukins-1, -2, and -3 Sources Macrophages, T lymphocytes T lymphocytes, endothelial cells, fibroblast Macrophages Macrophages, endothelial cells, T lymphocytes Macrophages, endothelial cells, fibroblasts, platelets Primary Effects Lymphocyte activation, PG production Macrophage & granulocyte activation PG production Many GM-CSF TNF-alpha Interferons PDGF Fibroblast chemotaxis, proliferation
Slide 5: Rheumatoid arthritis  Chronic inflammation → pain & destruction of bone & cartilage An autoimmune disease 
Slide 6: Goals of Therapy - Relief of pain - Reduction of inflammation Protection of articular structures Maintenance of function Control of systemic involvement
Slide 7: 5 General Approaches  NSAIDs and simple analgesics – – to control the s/s of local inflammatory process Minimal effect on the progression of the disease - Groups of NSAIDs Salicylic acid derivatives (Aspirin, Na salicylate, choline Mg++ trisalicylate, salsalate, diflunisal, sulfasalazine) Para-chlorobenzoic acid derivatives or indoles (Indomethacin, Sulindac) Pyrazolone derivatives (Phenylbutazone) Arylpropionic acid (Ibuprofen, Flurbiprofen, Ketoprofen, Fenoprofen, Naproxen, Oxaprozin)
Slide 8: 5 General Approaches  NSAIDs and simple analgesics – – to control the s/s of local inflammatory process Minimal effect on the progression of the disease - Groups of NSAIDs Fenamates/Anthranilic acids (Mefenamic Acid, Meclofenamic acid) Enolic acids/Oxicams (Piroxicam) Heteroaryl/Penylacetic acids (Diclofenac Sodium, Tolmetin, ketorolac) Alkalones (Nabumetone) Selective COX-2 inhibitors (Celecoxib, Rofecoxib, Meloxicam) Para-aminophenol (Acetaminophen)
Slide 9: 5 General Approaches  Glucocorticoids – – To suppress s/s of inflammation Retard the development & progression of bone erosions  DMARDs – – Methotrexate, sulfasalazin, hydroxychloroquine, gold salts, or D-penicillamine Have the capacity to decrease elevated levels of acute phase reactants → modify inflammatory component & its destructive capacity
Slide 10: 5 General Approaches  Biologics – – – – TNF-neutralizing agents: infliximab, etanercept, & adalimumab IL-1 neutralizing agents: anakinra Depletes B cells: rituximab Interferes T cell activation: abatacept  Immunosuppressive & Cytotoxic agents – Leflunomide, cyclosporine, azathioprine, cyclophosphamide  Shown to ameliorate the disease process
Slide 12: Types of Cyclooxygenases / Prostaglandin G/H synthase   COX 1 - involved in tissue hemeostasis COX 2 - responsible for the production of the prostanoid mediators of inflammation (IL-1 and TNF-α) COX 3 
Slide 13: Three major types of effects of NSAIDs  Anti-inflammatory Analgesic Antipyretic –   related to their primary action: inhibition of arachidonate cyclooxygenase, → inhibition of prostaglandin and thromboxanes.
Slide 14: Other Effects of NSAIDs  Strong O2-radical scavenging effects damage decrease tissue      Inhibit platelet aggregation except COX 2 selective inhibitors Gastric irritants Nephrotoxicity Hypertensive complications hepatotoxicity
Slide 15: NSAIDs: Pharmacokinetics    Weak organic acid, except Nabumetone Well absorbed food does not change their bioavailability, except Fenoprofen & Piroxicam Highly metabolized: CYP3A or CYP2C Renal excretion: most important route of final elimination Biliary excretion & reabsorption (enterohepatic circulation) Highly protein bound (~ 98%): albumin Found in synovial fluid     
Slide 16: Aspirin or Acetylsalicylic Acid (ASA) – Comes from the family of salicylates derived from salicylic acid – – – – Prototype drug Developed in 1899 by Adolph Bayer The oldest anti-inflammatory agent Rarely used as an anti-inflammatory medication
Slide 17: Aspirin or Acetylsalicylic Acid (ASA) Pharmacokinetics        Rapidly absorbed from the stomach & upper small intestine Peak plasma level: 1-2 hrs 80-90% protein bound t1/2: 15 minutes Cross BBB & placental barrier Undergoes hepatic metabolism Excretion: kidneys
Slide 18: Aspirin or Acetylsalicylic Acid (ASA) Mechanisms of Action - Inhibits prostaglandin synthesis - Irreversibly blocks the enzyme cyclooxygenase (PG synthase) . Pharmacological Properties & Therapeutic indications: - anti-inflammatory effects - analgesic effects - antipyretic effects - Platelet effects - Uricosuric effects . Dosage: children: 50-75mg/kg/day adult: 325-650mg p.o. q 4 hrs
Slide 19: Aspirin or Acetylsalicylic Acid (ASA) Adverse Effects          Gastric upset Salicylism  vomiting, tinnitus, decreased hearing, & vertigo Hyperpnea Respiratory alkalosis  later acidosis supervenes Glucose intolerance Cardiotoxicity Increases uric acid levels Elevation of liver enzymes, hepatitis, decreased renal function, bleeding, rashes, asthma Reye’s syndrome
Slide 20: Aspirin or Acetylsalicylic Acid (ASA) Contraindications        Pregnancy Severe hepatic damage Vitamin K deficiency Hypoprothrombinemia Hemophilia PUD Viral (chickenpox & influenza)
Slide 21: Aspirin or Acetylsalicylic Acid (ASA) Drug Interactions       Indomethacin, Naproxen Ketoprofen, Fenoprofen Warfarin Sulfonylureas, Methotrexate Spironolactone Penicillin
Slide 22: COX-2 Selective Inhibitors  Were developed in an attempt to inhibit PG synthesis by the COX-2 iso-enzyme without affecting the action of COX-1 found in the GIT, kidneys & platelets At usual dose: no impact on platelet aggregation Do not offer cardio-protective effects Suggested a higher incidence of CV thrombotic events: rofecoxib & valdecoxib   
Slide 23: COX-2 Selective inhibitors Drugs Absorption Celecoxib 20-30% (affected by food) 11 hrs high Etoricoxib 83% Meloxicam Slowly absorb Valdecoxib/ Rofecoxib 1-2 hours Parecoxib 15 minutes (IV, IM) Lumiracoxib Rapid & well absorbed 24 hrs Half-life Protein binding Peak Plasma concentration Metabolism Excretion 20-26% 20% 8-11 hours 1-3 hrs CYP2C9 Affected by hepatic impairment dyspepsia liver kidney 40% decreased in elderly Slightly less ulcerogenic MI, CVA/HTN, CHF, StevensJohnson Side Effects Inc BP, MI, inc transaminases
Slide 24: Non-selective COX inhibitors (Heteroacyl/Phenylacetic acid derivative) Drugs Absorption Half-life Protein-binding Peak Plasma Concentration Bioavailability Metabolism Excretion Side effects 30-70% CYP3A4 & CYP2C9 Biliary (30%) & urine (65%) GI distress, Occult GI bleeding, Gastric ulceration,  aminotransferases Diclofenac rapid 1-2 hours 99% Etodolac Rapid, well absorbed 7 hours 99% Ketorolac Rapid (oral, IM), IV, oral rinse, topical 4-6 hours 99% 30-50 min. 80% 80% Urine (90%) Somnolence, dizziness, HA, dyspepsia, nausea pain at injection site
Slide 25: Non-selective COX inhibitors (Salicylic acid derivative) Diflunisal  Derived from salicylic acid Not metabolized to salicylic acid or salicylate Undergoes enterohepatic cycle with reabsorption of its glucoronide metabolite T1/2: 13 hours Uses: cancer pain with bone metastases & pain control in dental (3rd molar) surgery Preparation: 2% oral ointment     
Slide 26: Non-selective COX inhibitors (Propionic acid derivative) Drugs Absorption Half-life Protein-binding Peak Plasma Concentration Metabolism Excretion Side effects Drug Interactions Fenoprofen Rapid, incomplete 2-4 hours 99% 2 hours Extensive hepatic urine Interstitial nephritis, GI irritation, tinnitus, rash pruritus Flurbiprofen Well absorbed 0.5-4 hours Ibuprofen Ketoprofen 1-2 hours 99% 1-3 hours 99% 1-2 hours 1-2 hours Extensive hepatic CYP2C8 & CYP2C9 urine GI irritation & bleeding GIT & CNS (30%) Probenecid
Slide 27: Non-selective COX inhibitors (Propionic acid derivative) Drugs Absorption Half-life Protein-binding Peak Plasma Concentration Bioavailability Metabolism Excretion Side effects UGIB, allergic pneumonitis, leukocytoclastic vasculitis, pseudoporphyria Naproxen Tiaprofen Caprofen Oxaprozin 12 hours high 1-2 hours, 2-4 hours (elderly) 10-16 hours 50-60 hours CYP2C9, less in CYP1A2 & CYP2C8
Slide 28: Non-selective COX inhibitors (Para-chlorobenzoic acid derivative or indole) Indomethacin   Introduced in 1963 A more potent analgesic, antipyretic & antiinflammatory agent than ASA May also inhibit phospholipase A & C Reduce PMN migration Decrease T & B cells proliferation   
Slide 29: Non-selective COX inhibitors (Para-chlorobenzoic acid derivative or indole) Drugs Absorption Peak concentration Metabolism Excretion Side effects Drug interaction Indomethacin Rapid & almost complete 2 hours Liver Urine, bile, feces GIT, CNS, hematologic, psychosis w/ hallucination Furosemide, thiazide, beta blockers, ACEI, probenecid Sulindac 90% absorption 1 hour, t1/2: 7 hours First pass hepatic, sulfide, active metabolite Urine, bile, feces GIT, CNS, hematologic, renal, allergic reactions
Slide 30: Non-selective COX inhibitors (Fenamates/Anthranilic Acid) Meclofenamate & Mefenamic acid  Inhibit both COX & phospholipase A2 Peak plasma level: 30-60 min t1/2: 1-3 hrs SE: LBM, abdominal pain (meclofenamate) CI: pregnancy, children DI: oral anticoagulants Indications: Primary Dysmenorrhea      
Slide 31: Non-selective COX inhibitors (Alkalones) Nabumetone   The only nonacid NSAID, causes less gastric damage Converted to the active metabolites in the liver, 6-methoxy-2 naphthylacetic acid Given as a ketone prodrug Dose: 1000 mg t1/2: > 24 hrs Does not undergo enterohepatic circulation Causes pseudoporphyria & photosensitivity     
Slide 32: Non-selective COX inhibitors (Pyrazolone derivative) Drugs Properties Phenylbutazone Withdrawn from the market Azapropazone Structurally related to phenylbutazone 12-16 hours aplastic anemia, agranulocytosis Half-life Toxicities
Slide 33: Non-selective COX inhibitors (Oxicams/Enolic acid) 19. Piroxicam  Inhibits PMN leukocyte migration, decreases O2 radical production, & inhibits lymphocyte function Inhibits proteoglycanase & collagenase Mean t1/2: 50-60 hrs Dosing: o.d. or every other day   
Slide 34: Non-selective COX inhibitors (Oxicams/Enolic acid) 19. Piroxicam  Pharmacokinetics: – – – – – – Rapidly absorbed from the stomach & upper intestine Peak plasma concentration: 1 hr Extensively metabolized to inactive metabolites 99% protein bound Elimination: renal – 5% unchanged Toxicity: GI symptoms, dizziness, tinnitus, HA & rash, increased incidence of PUD and bleeding
Slide 35: Non-selective COX inhibitors (Oxicams/Enolic acid) 20. Tenoxicam Half-life: 72 hours Similar to piroxicam  
Slide 36: Other analgesics ACETAMINOPHEN – – – – – Active metabolite of phenacetine A weak PG inhibitor No significant anti-inflammatory effect For the treatment of mild to moderate pain Antipyretic effect
Slide 37: Other analgesics ACETAMINOPHEN  Pharmacokinetics: – – – – – – – – Administered orally Absorption: related to rate of gastric emptying Peak blood concentration: 30-60 min Slightly protein bound Partially metabolized by hepatic microsomal enzyme  acetaminophen SO4 & glucuronide Excretion: unchanged < 5% A minor but highly active metabolite (N-acetyl-pbenzoquinone) is important  liver & kidney toxicity t1/2: 2-3 hrs
Slide 38: Other analgesics ACETAMINOPHEN  Adverse effects: – – – – Mild increase in hepatic enzymes Dizziness, excitement & disorientation Ingestion of 15gm: fatal  death caused by hepatotoxicity with centrilobular necrosis & sometimes with acute renal tubular necrosis Symptoms of early hepatic damage: N/V, diarrhea, abdominal pain  Antidote: N-acetylcysteine (sulfhydryl groups)   Caution: liver disease Dosage: 325-500mg q.i.d.
Slide 39: CORTICOSTEROID DRUGS  Capable of slowing the appearance of new bone erosions Known to inhibit phospholipase A2 Shown to selectively inhibit the expression of COX-2 SE: fracture, infections, cataracts Prep: oral, intra-articular    
Slide 40: DISEASE-MODIFYING ANTIRHEUMATIC DRUGS (DMARDS)  Might arrest or at least slow the progression of bone & cartilage destruction Effects may take 6 weeks to 6 months to become evident Exert minimal direct nonspecific anti-inflammatory or analgesic effects Frequent improvement in serologic evidence of disease activity, titers of RF & CRP and ESR decline   
Slide 41: METHOTREXATE  MOA: inhibition of aminoimidazolecarboxamide ribonucleotide (AICAR) transformylase & thymidylate synthase, with secondary effects on PMN chemotaxis plus enhanced adenosine release Absorption: 70% after oral administration Excretion: urine & bile Dose: 7.5 - 25mg/wk (oral, SC or IM) Toxicities: nausea, mucosal ulcers, dose-related hepatotoxicity, “hypersensitivity” lung reaction, pseudolymphomatous reaction Folic acid & leucovorin     
Slide 42: SULFASALAZINE  Consists of sulfapyridine & 5-amino-salicylic acid connected by diazo bond Metabolized by bacteria in the colon Have some anti-inflammatory action by O2 radical scavenging & inhibition of prostanoids and inhibit immune reactivity t1/2: 6-17 hrs Dose: 2-3g/d Uses: RA, juvenile arthritis & ankylosing spondylitis     
Slide 43: CHLOROQUINE, HYDROXYCHLOROQUINE   Used for the treatment of RA & SLE MOA: unclear – – – – They suppress the responsiveness of T lymphocytes to nitrogens decrease leukocyte chemotaxis stabilize lysosomal membranes inhibit DNA & RNA synthesis and trap free radicals    Effects are seen after 12-24 weeks Other indications: juvenile chronic arthritis, Sjogren’s syndrome Toxicity: ocular, dyspepsia, N/V, abdominal pain, rashes, nightmares
Slide 44: GOLD  Prep: auranofin – oral aurothiomalate & aurothioglucose – parenteral 95% protein-bound Concentrate in synovial membrane, liver, kidney, spleen, adrenal glands, LN, & BM Peak serum level: 2-6 hrs Excretion: 40% within a week = 2/3-urine; 1/3-feces Total body t1/2 (IM) – 1 year     
Slide 45: GOLD  Mechanisms of action: – alters the morphology and functional capabilities of human macrophages inhibition of lysosomal enzyme activity reduction of histamine release from mast cells suppression of phagocytic activity of the PMN leukocytes Aurothiomalate reduces the number of circulating lymphocytes Auranofin inhibits the release of PGE2 from synovial cells and the release of leukotrienes B4 & C4 from PMN leukocytes – – – – –
Slide 46: GOLD  Indications: – – – – Active RA Active inflammation & erosive changes RA with Sjogren’s syndrome Juvenile RA  CI: history of previous toxicity from the drug, pregnancy, serious liver & renal impairment & blood dyscrasia
Slide 47: GOLD  Adverse effects: – Dermatitis - 15-20% (most common) – – – – Thrombocytopenia, leukopenia, pancytopenia – 1-10% Aplastic anemia – rare but fatal Proteinuria  nephrotic syn – 8-10% Stomatitis, metallic taste, skin pigmentation, enterocolitis, cholestatic jaundice, peripheral neuropathy, pulmonary infiltrates, & corneal deposition of gold Nitritoid reaction (sweating, faintness, flushing, & headache) GI disturbances (LBM) – –
Slide 48: PENICILLAMINE  Pharmacodynamics: – – Interact with lymphocytes membrane receptors Interfere with the synthesis of DNA, collagen, & mucopolysaccharides  Parmacokinetics: – – – – – A metabolite of penicillin Is an analog of amino acid cysteine Absorption: half of the orally administered, enhanced after 1.5 hrs p.c. Excretion: urine & feces in 24 hrs Dose: 125-250mg daily for 1-3 months, 1.5 hrs p.c.
Slide 49: PENICILLAMINE  Adverse effects: – – – – – – – – – – – Decrease RF titer Impedes absorption of many drugs Inhibition of wound healing, muscle & blood vessel damage Proteinuria – 20% Immune complex nephritis – 4% Leukopenia & thrombocytopenia  aplastic anemia Skin & mucosal membrane reactions Drug fever associated with cutaneous eruption Any of these maybe seen: myasthenia gravis, hemolytic anemia, thyroiditis, Goodpasture’s syndrome & SLE Loss of taste perception or metallic taste, anorexia, N/V Mammary hyperplasia, alopecia, & psychologic changes
Slide 50: PENICILLAMINE  Contraindications: – – Pregnancy Renal insufficiency  Drug Interactions: – – – Gold Cytotoxic drugs Phenylbutazone
Slide 51: Biologics  Bind & neutralize TNF – – – Etanercept – a TNF type II receptor fused to IgG1 Infliximab – a chimeric mouse/human antibody to TNF Adalimumab – a fully human antibody to TNF    L-1 neutralizing agent – Depletes B cells – Anakinra Interferes with T cell activation – rituximab abatacept
Slide 52: Biologics that bind & neutralize TNF Drugs Etanercept Infliximab Adalimumab Peak Serum Concentration Route of Administration Half-life 72 hour 25mg SC b.i.d. 3 or 10mg/kg at 0, 2 & 6 weeks I V infusion 8-12 days 40mg every other week SC 10-20 days Side Effects Injection site reactions, activation of latent pulmonary tuberculosis Upper RTI, nausea, headache, sinusitis, rash & cough with MTX Opportunistic infections, leukopenia, vasculitis, lupus
Slide 53: Biologics Drugs MOA Anakinra A recombinant IL-1 receptor antagonist that competitively blocks the binding of IL-1β & IL-1α Rituximab A chimeric monoclonal antibody that targets CD20 B lymphoctyes Abatacept Inhibits the activation of T cells by inhibiting the binding to CD28 and CD80/86 I V infusion, 3 initial dose (day 0, week 2, week 4), then followed by monthly infusion 13-16 days, May or may not be combined with MTX, but not with anti-TNF increased risk of infection, hypersensitivity reactions Route/Dose Half-life/Drug interaction Side Effects Not recommended to combined with anti-TNF 2 I V infusions 2 weeks apart May be combined with MTX injection site reaction related to transfusion reaction
Slide 54: Immunosuppressive Therapy  These drugs have been reserve for patients who have clearly failed therapy with DMARDs and biologics Effective in the treatment of RA 
Slide 55: AZATHIOPRINE  Acts through its major metabolite, 6-thioguanine suppresses inosinic acid synthesis and B & T cell functions, immunoglobulin production & IL-2 secretion Dosage: 2mg/kg/d Other indications: SLE, Behcet’s syndrome, psoriatic arthritis, reactive arthritis, polymyositis Toxicities: BM suppression, GI disturbances, increased in risk for infections and malignancy   
Slide 56: LEFLUNOMIDE  A77-1726 (active metabolite) inhibits dihydroorotate dehydrogenase  decrease de novo RNA synthesis and lower levels of rUMP  translocation of p53 to nucleus  inhibits autoimmune T cell proliferation & production of autoantibodies by B cells Increases the mRNA level of IL-10 receptor, decreases IL-8 receptor type A mRNA concentrations & blocks TNF-dependent nuclear factor-kappa B activation 
Slide 57: LEFLUNOMIDE  Pharmacokinetics: – – – – – – – Orally active molecule MW: 270 Absorption: rapidly & nearly 100% plasma t1/2: 15 days Strong protein binding Enterohepatic circulation Excretion: bile   DI: cholestyramine SE: diarrhea, elevation of liver enzymes
Slide 58: CYCLOSPORINE  Acts through IL-2 & TNF-a suppression, mediated through T cell effects Absorption: erratic Bioavailability: 30%, grape fruit juice increases by 62% Metabolized in the liver Dosage: 3-5mg/kg/d Toxicities: nephrotoxicity, HTN, hyperkalemia, hepatotoxicity, gingival hyperplasia, & hirsutism     
Slide 59: CYCLOPHOSPHAMIDE  MOA: through it active metabolite, phosphoramide mustard, cross-links DNA & prevents cell replication, it suppresses T & B cell functions by 30-40% Metabolized in the liver Given orally at 2mg/kg/d Toxicities: infertility, BM suppression, hemorrhagic cystitis, bladder Ca  acrolein Other indications: SLE    
Slide 60: Mycophenolate mafetil     Active form: mycophenolic acid Inhibits cytosine monophosphate dehydrogenase Inhibits T-cell lymphocyte proliferation Interferes with leucocyte adhesion to endothelial cells through inhibition of E-selectin, P-selectin, & IC adhesion molecule1 Indication: SLE, vasculitis, Wagener’s granulomatosis, RA Dosage: 2 g/day Adverse effects: GI, hematopoietic & hepatic   
Slide 61: IMMUNOADSORPTION APHERESIS  Mechanism of action: – Down-regulation of B cell function through the release of small amounts of staphylococcal protein A complexed with immunoglobulins  Median duration of response: 6 months SE: chills – 30%, musculoskeletal pain – 15%, HA & nausea – 20-30%, joint pains & swelling – 30% 
Slide 62: DRUGS USED IN GOUT (COLCHICINE)  Dramatically relieves pain, by binding to IC protein tubulin  preventing polymerization into microtubules  inhibition of leukocyte migration & phagocytosis Absorption: readily, oral Peak serum level: 2 hrs Excretion: intestinal tract & urine   
Slide 63: DRUGS USED IN GOUT (COLCHICINE)  Indication: gouty arthritis, acute Mediterranean fever, sarcoid arthritis, hepatic cirrhosis Dosage: 0.5-1 mg q 2 hrs SE: LBM, N/V, abdominal pain, hair loss, BM depression, peripheral neuritis, myopathy Acute intoxication: burning throat pain, bloody LBM, shock, hematuria, oliguria, CNS depression   
Slide 64: NSAIDs in GOUT  Inhibit urate crystal phagocytosis Indomethacin is the agent most often used – 50 mg q 6 hrs  reduced to 25mg t.i.d or q.i.d. for 5 days ASA, salicylates, tolmetin are not effective for gouty episodes Oxaprozin, lowers serum uric acid, but not given to patients with uric acid stone   
Slide 65: URICOSURIC AGENTS (Probenecid & Sulfinpyrazone)  Act at the anionic transport sites of the renal tubule Employed to decrease the body pool of urates Reabsorption of uric acid in the proximal tubule is decreased Probenecid: completely reabsorbed by renal tubules & metabolized slowly Sulfinpyrazone: rapidly excreted by the kidneys    
Slide 66: Probenecid & Sulfinpyrazone Adverse Effects, CI & Cautions  AE: GI irritation, allergic dermatitis, nephrotic syndrome (probenecid), aplastic anemia CI & C: stone formation Dosage: probenecid – 0.5 gm orally in divided doses, sulfinpyrazone – 200 mg daily  
Slide 67: ALLOPURINOL  Reduce uric acid synthesis by inhibiting xanthine oxidase and increasing uric acid excretion Absorption: 80%, oral Given o.d. Indications: chronic tophaceous gout, uric acid urine (24hrs) > 600700mg, allergic reactions to probenecid & sulfinyrazone, renal impairment, grossly elevated serum uric acid levels AE: N/V, diarrhea, peripheral neuritis, necrotizing vasculitis, BM depression, aplastic anemia, hepatic toxicity, interstitial nephritis, allergic skin reaction, cataracts    
Slide 68: Febuxostat   First non-purine inhibitor of xanthine oxidase More than 80% absorbed following oral administration Maximum concentration: 1 hour Extensively metabolized in the liver Excreted in the urine   
Slide 69: Febuxostat  Pharmacodynamics: – Potent & selective inhibitor of xanthine oxidase → reduces the formation of xanthine & uric acid  Dose: 80mg, 120mg, 300mg daily Adverse effects: liver function abnormalities, diarrhea, headache nausea 
Slide 71: COX-2 Selective inhibitors 1. Celecoxib       Highly selective COX-2 inhibitor Absorption: 20-30% decreased by food t1/2: 11 hrs Highly protein bound Metabolized by CYP2C9 Clearance affected by hepatic impairment
Slide 72: COX-2 Selective inhibitors 1. Celecoxib  Effective dose: 100-200mg b.i.d. Does not affect platelet aggregation DI: warfarin, fluconazole, lithium AR: dyspepsia   
Slide 73: COX-2 Selective inhibitors 2. Etoricoxib      a bipyridine derivative Incompletely absorbed: 83% t1/2: 20-26 hours Extensively metabolized followed by renal excretion Uses: RA, OA, Gouty arthritis, Musculoskeletal pain, primary dysmenorrhea
Slide 74: COX-2 Selective inhibitors 3. Meloxicam   An enolcarboxamide Slightly COX-2 selective, slightly less ulcerogenic Known to inhibit thromboxane A2 Slowly absorbed t1/2: 20 hrs Clearance: 40% decreased in elderly Dose: 7.5-15mg/d for RA & OA     
Slide 75: COX-2 Selective inhibitors 4. Valdecoxib      A diaryl-substituted isoxazole Absorbed rapidly: 1-2 hours Peak serum concentration is delayed by the presence of food Undergoes extensive hepatic metabolism elevates blood pressure, elevate the risk of heart attack & stroke Withdrawn from the market in U.S.A. 
Slide 76: COX-2 Selective inhibitors 5. Rofecoxib  Introduced in 1999 Increases incidence of serious thromboembolic events Withdrawn from the market worldwide  
Slide 77: COX-2 Selective inhibitors 6. Parecoxib     Prodrug of valdecoxib Administered parenterally: IV & IM Absorbed rapidly: 15 minutes Converted by deoxymethylation to valdecoxib (active drug) Effective analgesic for peri-operative period 
Slide 78: COX-2 Selective inhibitors 7. Lumiracoxib       A weak acid Rapid & well absorbed Peak plasma concentration: 1-3 hours Half-life in synovial fluid: 24 hours elevates BP, incidence of myocardial infarction elevates hepatic transaminases
Slide 79: Non-selective COX inhibitors (Heteroacyl/Phenylacetic acid derivative) 1. Diclofenac        Rapidly absorbed following oral administration 99% protein bound 30-70% systemic bioavailability  first pass hepatic metabolism t1/2: 1-2 hrs Accumulates in synovial fluid  t1/2 of 2-6 hrs Metabolized by CYP3A4 & CYP2C9 30% biliary clearance, urine (65%)
Slide 80: Non-selective COX inhibitors (Heteroacyl/Phenylacetic acid derivative) 1. Diclofenac  Adverse effects: – – – – – GI distress Occult GI bleeding Gastric ulceration Impair RBF & GFR (150mg/d) Elevates serum aminotransferases Preparations: ophthalmic, dermatologic, IM administration, oral mouth wash, topical gel, rectal suppository
Slide 81: Non-selective COX inhibitors (Heteroacyl/Phenylacetic acid derivative) 2. Etodolac    Slightly more COX-2 selective, with COX-2:COX-1 activity ratio of 10 Clinical uses: postoperative analgesia, osteoarthritis, rheumatoid arthritis SE: GI irritation & ulceration (less)  Pharmacokinetics: – – – – – – – Rapidly well absorbed 80% bioavailability Strongly bound to plasma proteins (99%) Enterohepatic circulation t1/2: 7 hrs Excreted in the urine Dosage: 200-400mg/d t.i.d or q.i.d.
Slide 82: Non-selective COX inhibitors (Heteroacyl/Phenylacetic acid derivative) 3. Ketorolac  Potent analgesic with moderate antiinflammatory & antipyretic effects Indications: post-surgical pain, chronic pain, inflammatory conditions of the eye, seasonal allergic conjunctivitis  topical 
Slide 83: Non-selective COX inhibitors (Heteroacyl/Phenylacetic acid derivative) 3. Ketorolac  Pharmacokinetics: – – – – – – Rapidly absorbed after oral or IM administration, also given I V Peak concentration: 30-50 min. 80% oral bioavailability, almost totally protein bound t1/2: 4-6 hrs Metabolized to active & inactive forms Excreted in the urine (90%)
Slide 84: Non-selective COX inhibitors (Propionic acid derivative) 5. Fenoprofen  t1/2: 2-4 hrs Given q.i.d. Adverse effects: nephrotoxicity (interstitial nephritis), nausea, dyspepsia, peripheral edema, rash, pruritus, CNS & CVS effects and tinnitus Rarely used   
Slide 85: Non-selective COX inhibitors (Propionic acid derivative) 6. Flurbiprofen         Also affect TNF-a & nitric oxide synthesis t1/2: 0.5-4 hrs Extensive hepatic metabolism Dosages: 200-400mg/day Ophthalmic formulation  inhibition of intra-operative miosis, I V  effective for peri-operative analgesia, lozenge form for sore throat SE: GI symptoms, cogwheel rigidity, ataxia, tremor &
Slide 86: Non-selective COX inhibitors (Propionic acid derivative) 7. Ibuprofen       Dose: 2400mg daily 99% protein bound Terminal t1/2: 1-2 hrs Extensively metabolized in CYP2C8 & CYP2C9 in the liver SE: GI irritation & bleeding CI: nasal polyps, angioedema, bronchospastic reactivity to ASA, rash, pruritus, tinnitus, dizziness, HA, aseptic meningitis, fluid retention, agranulocytosis, aplastic anemia, ARF, interstitial nephritis, nephrotic syndrome
Slide 87: Non-selective COX inhibitors (Propionic acid derivative) 8. Ketoprofen  Inhibits both cyclooxygenase & lipoxygenase Rapidly absorbed Elimination t1/2: 1-3 hrs, metabolized in the liver (glucuronide) DI: probenicid Dosage: 100-300mg/day Indication: RA, OA, GA, dysmenorrhea AE: GIT & CNS      
Slide 88: Non-selective COX inhibitors (Propionic acid derivative) 9. Naproxen     Elimination serum t1/2: 12 hrs High albumin binding Metabolism: CYP2C9, less in CYP1A2 & CYP2C8 Prep: SR formulation, oral suspension, topical & ophthalmic solution AE: UGIB, allergic pneumonitis, leukocytoclastic vasculitis, & pseudoporphyria 
Slide 89: Non-selective COX inhibitors (Propionic acid derivative) 10. Tiaprofen Has a short serum half-life: 1-2 hours, 2-4 hours in elderly Inhibits renal uric acid reabsorption → decrease serum uric acid slightly Preparations: oral & IM   
Slide 90: Non-selective COX inhibitors (Propionic acid derivative) 11. Caprofen – Half-life: 10-16 hours
Slide 91: Non-selective COX inhibitors (Propionic acid derivative) 12. Oxaprozin  t1/2: 50-60 hrs Does not undergo enterohepatic circulation Given o.d. Is a mild uricosuric agent   
Slide 92: Non-selective COX inhibitors (Para-chlorobenzoic acid derivative or indole) 13. Indomethacin  Pharmacokinetics: – – – Rapidly & almost completely absorbed from GIT Peak concentration: 2 hrs Metabolism: liver & extensive enterohepatic circulation Excretion: bile, urine, feces –
Slide 93: Non-selective COX inhibitors (Para-chlorobenzoic acid derivative or indole) 13. Indomethacin  Drug interactions: – Probenecid – Furosemide – Thiazide – Beta adrenergic blocking agents – ACEI
Slide 94: Non-selective COX inhibitors (Para-chlorobenzoic acid derivative or indole) 13. Indomethacin  Therapeutic uses: – – – – – – – – Rheumatic conditions Gout & ankylosing spondylitis Patent ductus arteriosus Sweet’s syndrome Juvenile rheumatoid arthritis Pleurisy Nephrotic syndrome Tocolytic agent
Slide 95: Non-selective COX inhibitors (Para-chlorobenzoic acid derivative or indole) 13. Indomethacin  Adverse effects: – – – – Gastrointestinal effects (abdominal pain, diarrhea, GI hemorrhage, pancreatitis) Headache, dizziness, confusion, depression Psychosis with hallucination Thrombocytopenia, aplastic anemia, hyperkalemia  Contraindications: – – – – Nasal polyps, Angioedema, Asthma Renal failure Enterocolitis hyperbilirubinemia
Slide 96: Non-selective COX inhibitors (Para-chlorobenzoic acid derivative or indole) 14. Sulindac  A sulfoxide prodrug Reversibly metabolized to active metabolite sulfide  more potent as cyclooxygenase inhibitor , enterohepatic recycling prolongs duration of action: 12-16 hrs, excreted in bile, urine & feces Metabolized to an inactive sulfone  
Slide 97: Non-selective COX inhibitor (Para-chlorobenzoic acid derivative or indole) 14. Sulindac  Pharmacokinetics: – – – – 90% absorbed after oral administration Peak concentration: 1 hr t1/2: 7 hrs First pass kinetics  Therapeutic indications: – – – – – – Rheumatoid arthritis Suppresses familial intestinal polyposis Ankylosing spondylitis Osteoarthritis Acute Gout Tocolytic agent
Slide 98: Non-selective COX inhibitors (Para-chlorobenzoic acid derivative or indole) 14. Sulindac  Adverse effects: – – – – – – – GI side effects: abdominal pain & nausea CNS side effects: drowsiness, dizziness, HA, nervousness Skin rash & pruritus Transient elevations of hepatic enzymes Reversible renal failure & nephrotic syndrome Steven-Johnson syndrome agranulocytosis
Slide 99: Non-selective COX inhibitors (Pyrazolone derivative) Phenylbutazone  Withdrawn from the market in North American & most European markets Toxicity: aplastic anemia agranulocytosis 
Slide 100: Non-selective COX inhibitors (Pyrazolone derivative) 18. Azapropazone – Structurally related to phenylbutazone Half-life: 12-16 hours –
Slide 101: ANTI-TNF-ALPHA DRUGS (ETANERCEPT)  A recombinant fusion protein that consists of 2 soluble TNF p75 receptor moieties linked to Fc portion of human IgG Peak serum concentration: 72 hrs Dose: 25mg SC twice weekly Uses: psoriatic arthritis, juvenile chronic arthritis SE: injection site reactions – pain, erythema, swelling, itching (20-40%), activation of latent pulmonary tuberculosis    
Slide 102: ANTI-TNF-ALPHA DRUGS (INFLIXIMAB)  Monoclonal Ab that binds with high affinity to human TNF-a Given IV infusion Terminal t1/2: 8-12 days Dose: 3 or 10 mg/kg at 0, 2, & 6 wks SE: upper RTI, nausea, headache, sinusitis, rash & cough with MTX    
Slide 103: ANTI-TNF-ALPHA DRUGS (Adalimumab)       A fully human IgG1 anti-TNF monoclonal antibody Half-life: 10-20 DAYS Clearance is decreased by > 40% in the presence of methotrexate Indications: RA, ankylosing spondylitis, psoriatic arthritis Dose: 40mg every other week, SC Adverse effects: opportunistic infections, leukopenia, vasculitis, lupus
Slide 104: CHLORAMBUCIL  MOA: probably through its metabolic phenylacetic acid mustard, cross-links DNA, thereby preventing cell replication Bioavailability: 70% Completely metabolized Complete excretion within 24 hrs Other indications: SLE, vasculitis, Toxicities: BM suppression, infertility, risk of neoplasia & leukemia     
Slide 105: Anakinra  A recombinant IL-1 receptor antagonist that competitively blocks the binding of IL-1β & IL-1α shown to improve s/s of RA, decrease disability & slow progression of articular damage Major SE: injection site reaction Not recommended to combined with anti-TNF   
Slide 106: Rituximab  A chimeric monoclonal antibody that targets CD20 B lymphoctyes Given as 2 I V infusions 2 weeks apart May be combined with MTX SE: related to transfusion reaction   
Slide 107: Abatacept  Inhibits the activation of T cells by inhibiting the binding to CD28 and CD80/86 A fusion protein consisting of CTLA4 and the Fc portion of IgG1 Given I V infusion, 3 initial dose (day 0, week 2, week 4), then followed by monthly infusion Half-life: 13-16 days Adverse effects: increased risk of infection, hypersensitivity reactions May or may not be combined with MTX, but not with anti-TNF     