This document discusses several classes of drugs used to treat inflammation and pain. It covers:
1) NSAIDs like ibuprofen which reduce inflammation by inhibiting cyclooxygenase enzymes but can cause gastrointestinal adverse effects. Newer selective COX-2 inhibitors like celecoxib are less irritating to the stomach.
2) Disease-modifying antirheumatic drugs (DMARDs) treat rheumatoid arthritis by multiple mechanisms of action, though they have risks of hepatotoxicity and nephrotoxicity.
3) Drugs for gout including colchicine, allopurinol and febuxostat which reduce uric acid levels and thus treat gout flares and
This document discusses several classes of drugs used to treat inflammation and pain. It covers:
1) NSAIDs like ibuprofen which reduce inflammation by inhibiting cyclooxygenase enzymes but can cause gastrointestinal adverse effects. Newer selective COX-2 inhibitors like celecoxib are less irritating to the stomach.
2) Disease-modifying antirheumatic drugs (DMARDs) treat rheumatoid arthritis by multiple mechanisms of action, though they have risks of hepatotoxicity and nephrotoxicity.
3) Drugs for gout including colchicine, allopurinol and febuxostat which reduce uric acid levels and thus treat gout flares and
This document discusses several classes of drugs used to treat inflammation and pain. It covers:
1) NSAIDs like ibuprofen which reduce inflammation by inhibiting cyclooxygenase enzymes but can cause gastrointestinal adverse effects. Newer selective COX-2 inhibitors like celecoxib are less irritating to the stomach.
2) Disease-modifying antirheumatic drugs (DMARDs) treat rheumatoid arthritis by multiple mechanisms of action, though they have risks of hepatotoxicity and nephrotoxicity.
3) Drugs for gout including colchicine, allopurinol and febuxostat which reduce uric acid levels and thus treat gout flares and
Chapter 36 • Katzung, B. Basic and Clinical Pharmacology Content Outline Terms Terms Inflammation - complex response to cell NSAIDs › Chemistry injury that primarily occurs in › Pharmacokinetics vascularized connective tissue. › Pharmacodynamics/MOA - involves the immune › Adverse effects response › Choice of NSAIDs Antipyretic - drug that reduces fever COX-2-selective inhibitors Cyclooxygenase - enzymes responsible for Nonselective COX-1 inhibitors (COX), prostaglandin (COX) and DMARDS › Drugs lipoxygenase (LOX) leukotriene (LOX) synthesis › MOA Reye’s syndrome - rare syndrome of rapid liver › Pharmacokinetics degeneration and › Indications encephalopathy › Adverse effects - treated with aspirin during TNF – alpha blockers › Drugs viral infection › MOA Uricosuric agent - drug that increases the renal › Pharmacokinetics excretion of uric acid › Indications Enterohepatic - biliary excretion and › Adverse effects circulation reabsorption IL-1 inhibitors › Drugs › MOA › Pharmacokinetics › Indications › Adverse effects Glucocorticoids › Drugs › Indications › Adverse effects Others › Acetaminophen › Ketorolac › Tramadol Drugs used in gout › Colchicine › Uricosuric agents › Allopurinol › Febuxostat › Pegloticase
NSAIDs Effectively controls inflammatory pain
Chemistry & - several chemical classes Pharmaco- - only nabumetone (ketone prodrug) is a kinetics weak organic acids - most are well absorbed - Bioavailability is not affected by food - Most are highly metabolized by phase I phase II mechanisms - others by direct glucuronidation (phase II) alone. - NSAID metabolism – in the liver by CYP3A or CYP2C (P450) - Renal excretion - most important route for final elimination - Nearly all undergo biliary excretion and reabsorption (enterohepatic circulation) - highly protein-bound to albumin (~ 98%) - All NSAIDs - found in synovial fluid after Nonsteroidal Anti-Inflammatory Drugs, Disease-Modifying Antirheumatic Drugs, Nonopioid Analgesics, & Drugs Used in Gout Chapter 36 • Katzung, B. Basic and Clinical Pharmacology repeated dosing › NSAIDs - differentiated on the basis of - Drugs with short half-lives = remain in the toxicity and cost-effectiveness joints › Celecoxib – expensive, safest for - Drugs with long half-lives = disappear patients at high risk of GI bleeding but from synovial fluid may result to higher risk of Pharmaco- › NSAID anti-inflammatory activity = cardiovascular toxicity dynamics inhibition of prostaglandin biosynthesis › Celecoxib/nonselective NSAID + › Additional MOA = (1) inhibition of omeprazole or misoprostol = most chemotaxis, (2) down-regulation of IL-1 appropriate for patients at highest risk production (3) decreased production of for GI bleeding free radicals and superoxide (4) › Choice of an NSAID - requires a interference with calcium-mediated balance of efficacy, cost-effectiveness, intracellular events. safety, and numerous personal factors › NSAIDs are reversible inhibitors (other drugs being used, concurrent Effects/uses › All newer NSAIDs = analgesic, anti- illness, compliance, medical insurance) inflammatory, and antipyretic, inhibit › No best NSAID for all patients platelet aggregation (except COX-2 › 1 or 2 best NSAIDs for a specific selective inhibitors and nonacetylated person salicylates › NSAIDs decrease sensitivity of vessels to bradykinin and histamine = (1) affect lymphokine production from T lymphocytes, (2) reverse the vasodilation of inflammation › There is no evidence that it alters the course of arthritic disorder › Reduce the incidence of colon cancer when taken chronically › Most are effective in RA, seronegative spondyloarthropathies, OA, localized musculoskeletal syndromes, gout Adverse › NSAIDs = gastric irritants; effects associated with GI ulcers and bleeds › Newer NSAIDs = less GI irritant than aspirin › Nephrotoxicity = associated with prostaglandin inhibition = interference with the autoregulation of renal blood flow COX-2 SELECTIVE INHIBITORS (Coxibs) (modulated by prostaglandins) Hepatotoxicity – occurs with any NSAID Important › Developed to inhibit prostaglandin notes synthesis by the COX-2 isozyme AE similar 1. Central nervous system: Headaches, (inflammation) without affecting action for all tinnitus, dizziness, aseptic meningitis of COX-1 (GI tract, kidneys, and NSAIDs 2. Cardiovascular: Fluid retention, platelets) hypertension, edema, myocardial infarction, › Does not affect platelet aggregation Rare congestive heart failure (CHF). › inhibit COX-2-mediated prostacyclin 3. Gastrointestinal: Abdominal pain, synthesis in the vascular endothelium dyspepsia, nausea, vomiting, ulcers or › no cardioprotective effects bleeding. › Recommended doses = cause renal 4. Hematologic: Rare thrombocytopenia, toxicities neutropenia, aplastic anemia. › Incidence of cardiovascular thrombotic 5. Hepatic: Abnormal liver function test results and rare liver failure. DRUGS › 10–20 times more selective for COX-2 6. Pulmonary: Asthma. Celecoxib than for COX-1. › Half-life = 11 hrs 7. Skin: Rashes, all types, pruritus. › 27%= unchanged drug in urine 8. Renal: Renal insufficiency, renal failure, excretion hyperkalemia, proteinuria. › Metabolized by CYP2C9 (liver) Choice of › Tolmetin ineffective for gout › Drug interaction: warfarin NSAIDs › Aspirin – less effective for AS › Fewer endoscopic ulcers than other Nonsteroidal Anti-Inflammatory Drugs, Disease-Modifying Antirheumatic Drugs, Nonopioid Analgesics, & Drugs Used in Gout Chapter 36 • Katzung, B. Basic and Clinical Pharmacology NSAIDs › <1% = unchanged drug in urine › Sulfonamide = rashes excretion Meloxicam › Enolcarboxamide related to piroxicam › Used in OA and RA (300 mg; 2- › “Preferentially selective” not highly 3x/day or 500mg; 2x/day selective followed with maintenance of 00 › Fewer clinical GI symptoms mg/d) › inhibits synthesis of thromboxane A2 Flurbiprofen › Propionic acid derivative without affecting platelet function › S)(–) enantiomer inhibits COX › Half-life = 20 hrs nonselectively › <1% = unchanged drug in urine › Rat tissue - affect α (TNF-α) excretion (tumor necrosis factor) and nitric oxide synthesis › Extensive hepatic metabolism › No chiral conversion › Demonstrate enterohepatic circulation DOSAGE FORMS NONSELECTIVE COX INHIBITORS › Topical ophthalmic = Important notes › intraoperative miosis DRUGS › Phenylacetic acid derivative › IV = perioperative analgesia in Diclofenac › Half-life = 1.1 hrs minor ear, neck, and nose › <1% = unchanged drug in urine surgery excretion › Lozenge = sore throat › Less occurrence of GI ulceration AE: cogwheel rigidity, ataxia, tremor, › Drug interaction: diclofenac and and myoclonus misoprostol = decreased upper Ibuprofen › simple derivative of gastrointestinal ulceration; phenylpropionic acid induce diarrhea › equivalent to 4 g of aspirin in › Diclofenac + omeprazole = anti-inflammatory effect prevention of recurrent bleeding; › Half-life = 2 hrs common renal AE in high risk › <1% = unchanged drug in urine patients excretion › Impair renal blood flow and DOSAGE FORMS glomerular filtration rate › Oral (lower dose; OTC) = › Common occurrence of serum analgesic but not anti- aminotransferases elevation inflammatory DOSAGE FORMS: › Oral and IV = closing patent › 0.1% ophthalmic preparation - ductus postoperative ophthalmic › arteriosus in preterm infants inflammation, intraocular lens › Topical cream = absorbed into implantation, strabismus surgery fascia and muscle; primary knee › Topical gel containing 3% OA diclofenac = solar keratosis › Liquid gel (400mg) = postsurgical › Rectal suppository - preemptive dental pain analgesia and postoperative › Effects: decreases urine output nausea less and less fluid retention › EU = oral mouthwash and IM › Contraindication: Patients with Diflunisal › Derived from salicylic acid nasal polyps, angioedema, and › Undergoes an enterohepatic bronchospastic reactivity to cycle = reabsorption of its aspirin glucuronide metabolite = › AE: Aseptic meningitis (patients cleavage of glucuronide = with SLE), and fluid retention release active moiety › Drug interaction: Ibuprofen and › Half-life = 13 hrs, 2 divided aspirin = antagonizes the doses irreversible platelet inhibition › 3-9% = unchanged drug in urine induced by aspirin; limit excretion cardioprotective effects of Etodolac › Racemic acetic acid derivative aspirin; decrease total anti- › Half-life = 6.5 hrs (immediate) Nonsteroidal Anti-Inflammatory Drugs, Disease-Modifying Antirheumatic Drugs, Nonopioid Analgesics, & Drugs Used in Gout Chapter 36 • Katzung, B. Basic and Clinical Pharmacology inflammatory effect › Half-life = 58 hrs (very long) › AE: agranulocytosis and aplastic › 1-4% = unchanged drug in urine anemia excretion Indomethacin › indole derivative › No enterohepatic circulation › inhibit phospholipase A and C › Mildly uricosuric = mildly › reduce neutrophil migration, increases uric acid secretion › decrease T-cell and B-cell Piroxicam › Oxicam proliferation › High concentrations = inhibits › accelerate closure of patent polymorphonuclear leukocyte ductus arteriosus. migration, decreases oxygen › Tried for: Sweet’s syndrome, radical production, and inhibits juvenile RA, pleurisy, nephrotic lymphocyte function syndrome, diabetes insipidus, › Half-life = 57 hrs (long = 1x/day urticarial vasculitis, dosing) postepisiotomy pain, and › 4-10% = unchanged drug in prophylaxis of heterotopic urine excretion ossification in arthroplasty › Used in usual rheumatic › Half-life = 4-5 hrs indications › 16% = unchanged drug in urine › Higher dose (20 mg/d) = excretion increased incidence of peptic DOSAGE FORMS ulcer and bleeding › Ophthalmic preparation = Sulindac › Sulfoxide prodrug conjunctival inflammation; › Reversibly metabolized to active reduce pain after traumatic sulfide metabolite corneal abrasion › Enterohepatic cycling prolongs › Oral rinse = Gingival duration of action (12-16 hrs) inflammation › Used for rheumatic disease and › Epidural injections = pain relief in familial intestinal polyposis postlaminectomy syndrome › Inhibit the development of colon, › AE: GI = pancreatitis; headache, breast, and prostate cancer dizziness, confusion, and › Half-life = 8 hrs depression; renal papillary › 7% = unchanged drug in urine necrosis excretion Ketoprofen › propionic acid derivative › More severe AE: Stevens- › inhibits lipoxygenase Johnson epidermal necrolysis › Half-life = 1.8 hrs syndrome, thrombocytopenia, › <1% = unchanged drug in urine agranulocytosis, and nephrotic excretion syndrome › Drug interaction: Concurrent › AE: cholestatic liver damage administration of probenecid = Tolmetin › Not often used elevates ketoprofen levels and › Half-life = 1 hr (short) prolongs plasma half-life › 7% = unchanged drug in urine › Effective dosage = 100-300 mg/d excretion › Major adverse effects = GI tract › Ineffective in the treatment of and the central nervous system gout. Nabumetone › only nonacid NSAID Azapropazone, › Rarely used › ketone prodrug carprofen, › resembles naproxen in structure meclofenamate, › Half-life = >24 hrs (1x/day tenoxicam dosing) › No enterohepatic circulation › Renal impairment = doubled half- ASPIRIN life and 30% increase in area Important notes › rarely used as an anti- under the curve inflammatory medication › Less damaging to the stomach › antiplatelet effects › Needs higher dosages › acetylsalicylic acid › Very expensive NSAID › Long-term use at low dosage Oxaprozin › propionic acid derivative = lower incidence of colon cancer Nonsteroidal Anti-Inflammatory Drugs, Disease-Modifying Antirheumatic Drugs, Nonopioid Analgesics, & Drugs Used in Gout Chapter 36 • Katzung, B. Basic and Clinical Pharmacology MOA › irreversibly inhibits platelet legacy) products and biosimilar › COX (antiplatelet effect) DMARDs Pharmacokinetics › pKa = 3 ABATACEPT › T-cell–modulating biologic › Rapidly hydrolized (serum › MOA: inhibits the activation of T half-life = 15 mins) cells › Hydrolysis by esterases in – T cell will first interact with tissue and blood = acetic antigen-presenting cell (which acid and salicylate has CD80/CD86); a second › Salicylate = nonlinearly signal by CD28 is produced bound to albumin when T cell interaction with CD80/CD86 that will activate › Alkalinization of urine = T cell ↑ rate excretion of free – Abatacept (CTLA-4) binds to salicylate and water-soluble CD80 and 86 which stops conjugates binding with CD28 (no Clinical Uses › Decreases incidence of: second signal produced) = no 1. Transient ischemic attacks activation 2. unstable angina › Pharmacokinetics: Adult with RA 3. coronary artery thrombosis = 3 IV infusion “induction” dose 4. with myocardial infarction (even # weeks); followed with 5. thrombosis after coronary monthly infusions artery bypass grafting – Dose: based on body weight › Valuable in treating: › Available: subcutaneous preeclampsia-eclampsia formulation › Contraindicated in patients › JIA: induction sched at week with hemophilia 0,2,4; followed with infusion every Adverse effects › Main AE (antithrombotic 4 weeks dose): gastric upset › Indications: monotherapy or in (intolerance); gastric and combination with methotrexate or duodenal ulcers other DMARDs (severe RA/ PJIA) › Hepatotoxicity, asthma, › Most beneficial effects: psoriatic rashes, GI bleeding, and arthritis (PsA) patients renal toxicity › Patients screened for latent tuberculosis and viral hepatitis DISEASE-MODIFYING before starting ANTIRHEUMATIC DRUGS (DMARDs) › Live vaccines – avoided during; Important notes › Rheumatic Arthritis - progressive months after discontinuation immunologic disease › AE: slightly increased risk of – causes significant systemic infection of upper respiratory or effects, shortens life, and urinary tracts reduces mobility and quality › Possible increased lymphomas of life AZATHIOPRINE › csDMARD = major metabolite: 6- › Treatment goal: stop or slow the thioguanine. 6-Thioguanine progression by modifying the › MOA: suppresses inosinic acid disease synthesis, B-cell and T-cell › Disease-modifying therapies: function, immunoglobulin 1. conventional synthetic (cs) = production, and IL-2 secretion small molecule drugs › Pharmacokinetics: oral or 2. biologic (b) disease-modifying parenteral antirheumatic drugs = large- – Bimodal metabolism: Rapid molecule therapeutic agents metabolizers 4x faster (proteins). Often produced by – Metabolite production – recombinant DNA technology dependent on TPMT = › Gold salts – no longer patients with low/no TPMT recommended = significant are at high risk of toxicities and questionable myelosuppression (if dose is efficacy not adjusted) › bDMARDs - biological original (or › Indications: prevention of kidney Nonsteroidal Anti-Inflammatory Drugs, Disease-Modifying Antirheumatic Drugs, Nonopioid Analgesics, & Drugs Used in Gout Chapter 36 • Katzung, B. Basic and Clinical Pharmacology transplant rejection ribonucleotide synthesis and the – efficacy in PA, reactive arrest of stimulated cells in the G1 arthritis, polymyositis, SLE, phase of cell growth maintenance of remission in – Inhibits T-cell proliferation vasculitis, and Behçet’s and reduces production of disease autoantibodies by B cells – Used in (less effective): – 2nd effect: increases of IL-10 scleroderma receptor mRNA, decreased › AE: bone marrow suppression, GI IL-8 receptor type A mRNA, disturbances, ↑ infection risk. and decreased TNF-α– – Increase lymphomas dependent nuclear factor – fever, rash, and hepatotoxicity kappa B (NF-κB) activation signal acute allergic reactions › Pharmacokinetics: completely CHLOROQUINE › nonbiologic drugs mainly used for absorbed from the gut & malaria – Mean plasma half-life = 19 HYDROXYCH- › csDMARDs – rheumatic diseases days LOROQUINE › MOA: – Active metabolite: A77-1726 1. suppression of T-lymphocyte – Undergoes enterohepatic responses to mitogens recirculation 2. inhibition of leukocyte – Cholestyramine = enhance chemotaxis leflunomide excretion and 3. stabilization of lysosomal increases total (50%) enzymes › Indications: effective as 4. processing through the Fc- methotrexate in RA receptor – inhibition of bony damage 5. inhibition of DNA and RNA – Combined with methotrexate synthesis and leflunomide: 46.2% 6. trapping of free radicals ACR20 response › Pharmacokinetics: rapidly › AE: Diarrhea (cause of absorbed and 50% protein-bound discontinuation); Liver enzymes – Tissue-bound (eyes) elevation; mild alopecia, weight – Deaminated in liver gain, and increased blood – Blood elimination half-life = 4 pressure days › Leukopenia, thrombocytopenia › Indications: Dose-loading › Contraindicated: pregnancy increase rate of response METHOTREXA › synthetic nonbiologic – 3-6 mos = response TE antimetabolite – Used in SLE = decrease › first-line csDMARD for treating mortality and skin RA manifestations › MOA: Low doses = inhibition of – Used in: Sjögren’s syndrome amino-imidazolecarboxamide › AE: Ocular toxicity at high doses ribonucleotide (AICAR) – dyspepsia, nausea, vomiting, transformylase and thymidylate abdominal pain, rashes, and synthetase. nightmares. – inflammatory functions of CYCLOPHOSP › csDMARD neutrophils, macrophages, HAMIDE › major active metabolite is dendritic cells, and phosphoramide mustard = cross- lymphocytes are suppressed links DNA to prevent cell – Secondary effects on replication polymorphonuclear › MOA: suppresses T-cell and B- chemotaxis cell function (30-40%) – direct inhibitory effects on › Indications: 2 mg/kg for SLE, proliferation and stimulates vasculitis, Wegener’s apoptosis in immune granulomatosis, other severe inflammatory cells. rheumatic diseases – inhibits proinflammatory LEFLUNOMIDE › MOA: inhibits dihydroorotate cytokines linked to dehydrogenase = decrease in rheumatoid synovitis › Pharmacokinetics: orally or Nonsteroidal Anti-Inflammatory Drugs, Disease-Modifying Antirheumatic Drugs, Nonopioid Analgesics, & Drugs Used in Gout Chapter 36 • Katzung, B. Basic and Clinical Pharmacology parentally (SC or IM) infections – 70% absorbed after oral – Malignancy administration RITUXIMAB › MOA: chimeric monoclonal – Bioavailability decreased – antibody biologic agent that more than 25mg used targets CD20 B lymphocytes – metabolized to a less active – Reduces inflammation by hydroxylated product decreasing the presentation – Parent compound and of antigens to T lymphocytes metabolite – polyglutamated – inhibiting the secretion of within cells proinflammatory cytokines – Serum half-life = 6-9 hrs › Pharmacokinetics: Repeated 6- – excreted principally in the 9 mos urine; 30% - excreted in bile – Pretreatment 30 mins prior to › Indications: increased to the infusion (acetaminophen, most common dosing regimen for antihistamine, intravenous the treatment of RA glucocorticoids ) = decreases – ↑ effect = ↑ toxicity the incidence and severity of – Drug decreases the rate of infusion reactions appearance of new erosions › Indications: With methotrexate: – Used in: juvenile chronic treatment of moderately to arthritis, psoriasis, PA, AS, severely active RA polymyositis, dermatomyositis, – With glucocorticoids: treatment Wegener’s granulomatosis, of adult patients with giant cell arteritis, SLE, and granulomatosis with vasculitis polyangiitis and microscopic › AE: Most common toxicities: polyangiitis Nausea and mucosal ulcers › AE: Rash (first 1000mg) – – leukopenia, anemia, stomatitis, decreases 10% with second GI ulcerations, and alopecia infusion – Progressive dose-related – Decreased immunuglobulins = hepatotoxicity in the form of occurrence of infections enzyme elevation occurs – Serious, fatal, bacterial, frequently fungal, and viral infections – Cirrhosis – Reactivation of hepatitis B – Leucovorin – reduce incidence virus, fatal mucocutaneous of GI and liver function test reactions, cytopenias abnormalities – Cardiovascular events – Contraindicated in pregnancy SULFASALAZI › csDMARD metabolized to MYCOPHENOL › csDMARD NE sulfapyridine and 5-aminosalicylic ATE MOFETIL › converted to mycophenolic acid acid › MOA: inhibits inosine › MOA: Sulfapyridine = active monophosphate dehydrogenase moiety in treating RA = suppression of T- and B- – Suppression of T-cell lymphocyte proliferation responses to concanavalin – interferes with leukocyte and inhibition of in vitro B-cell adhesion to endothelial cells proliferation through inhibition of E-selectin, › Pharmacokinetics: 10–20% of P-selectin, and intercellular orally administered adhesion molecule 1 – A little undergoes › Indications: treatment of renal enterohepatic recirculation disease due to SLE – 5-aminosalicylic acid is – useful in vasculitis and unabsorbed Wegener’s granulomatosis – Half-life = 6-17 hrs › AE: nausea, dyspepsia, and › Indications: effective in RA abdominal pain, hepatotoxicity, – reduces radiologic disease leukopenia, thrombocytopenia, progression and anemia – uvenile chronic – increased incidence of – arthritis, PsA, inflammatory Nonsteroidal Anti-Inflammatory Drugs, Disease-Modifying Antirheumatic Drugs, Nonopioid Analgesics, & Drugs Used in Gout Chapter 36 • Katzung, B. Basic and Clinical Pharmacology bowel disease, AS, and monoclonal antibody spondyloarthropathy- › MOA: complexes with soluble associated uveitis TNF-α and prevents its interaction › AE: Discontinued = toxicity with p55 and p75 cell surface – nausea, vomiting, headache, receptors rash › Pharmacokinetics: Given – Hemolytic anemia, subcutaneously methemoglobinemia, › Drug interactions: Methotrexate thrombocytopenia, lupus – clearance is decreased; – Reversible infertility in men formation of human anti- but not in women monoclonal antibody is TOCILIZUMAB › MOA: binds to soluble and decreased membrane-bound IL-6 receptors, › Indications: approved for RA, and inhibits the IL-6-mediated AS, PsA, JIA, plaque psoriasis, signaling via these receptors. Crohn’s disease, and ulcerative – IL-6 responsible for T-cell colitis. activation, hepatic acute- – decreases the rate of phase protein synthesis, and formation of new erosions stimulation of the – effective as monotherapy and inflammatory processes in combination with involved in diseases methotrexate › Pharmacokinetics: Dose- Certolizumab › recombinant, humanized antibody dependent half-life Fab fragment conjugated to a – inhibiting IL-6 may restore polyethylene glycol (PEG) with CYP450 activities to higher specificity for human TNF-α levels › MOA: neutralizes membrane- – used in combination with bound and soluble TNF-α nonbiologic DMARDs or as › Pharmacokinetics: given monotherapy subcutaneously – Dosage in SJIA/PJIA = – Half-life = 14 days accounts for body weight – decreases the appearance of – Dosage modifications: anti-certolizumab antibodies. elevated liver enzymes, – Initial dose: 400mg; 200mg = neutropenia, and every other week; 400mg thrombocytopenia every 4 weeks › Indications: moderately to › Indications: treatment of adults severely active RA with moderately to severely active › AE: Serious infections = RA; monotherapy or in tuberculosis, fungal, viral, and combination with nonbiologic other opportunistic infections DMARDs; Crohn’s disease, active – Upper respiratory tract PsA, and active AS infections, headache, Etanercept › Recombinant fusion protein hypertension, elevated liver consisting of two soluble TNF p75 enzymes, GI perforation receptor moieties linked to the Fc – Neutropenia and reduction in portion of human IgG1 platelet › MOA: binds TNF-α molecules – Anaphylactic reaction and also inhibits lymphotoxin α. › Pharmacokinetics: Given TNF-α-BLOCKING AGENTS subcutaneously – drug is slowly absorbed Important notes › affects cellular function via – Peak concentration = 72 hrs activation of specific membrane- – Mean serum elimination half- bound TNF receptors life = 4.5 days › Five “legacy” bDMARDs – › Indications: treatment of RA, treatment of RA and other juvenile chronic arthritis, rheumatic diseases psoriasis, PsA, and AS. › Biosimilar biologics (bsDMARDs) – Decreases rate of formation – lower costs of new erosions relative to Adalimumab › fully human IgG1 anti-TNF Nonsteroidal Anti-Inflammatory Drugs, Disease-Modifying Antirheumatic Drugs, Nonopioid Analgesics, & Drugs Used in Gout Chapter 36 • Katzung, B. Basic and Clinical Pharmacology methotrexate alone develop antidrug antibodies = – used in other rheumatic interfere with drug efficacy syndromes › INCREASED risk of – such as scleroderma, gastrointestinal ulcers and large granulomatosis with bowel perforation including polyangiitis (Wegener’s diverticular and appendiceal granulomatosis), giant cell perforation. arteritis, Behçet’s disease, › Etanercept: lower activation of uveitis, and sarcoidosis. latent tuberculosis Golimumab › human monoclonal antibody with › Alopecia areata, hypertrichosis, a high affinity for soluble and and erosive lichen planus membrane-bound TNF-α › Cutaneous pseudo-lymphomas, › MOA: neutralizes the Nonspecific interstitial inflammatory effects produced by pneumonia, psoriasis, and TNF-α sarcoidosis-like syndrome, › Pharmacokinetics: administered leukopenia, neutropenia, subcutaneously thrombocytopenia, and – Half-life = 14 days pancytopenia – Used with methotrexate = increases golimumab serum OTHER DRUGS levels and decreases anti- USTEKINUMAB › MOA: IL-12 and IL-23 antagonist golimumab antibodies – part of both IL-12 and IL-23 = – 50 mg = treatment of RA, contributors to the chronic PsA, and AS inflammation in psoriasis – Higher dose – treatment of plaques, PsA, and Crohn’s ulcerative colitis disease › Indications: moderately to – prevents the binding of the severely active RA, PsA, AS and p40 subunit of both IL-12 and moderate to severe ulcerative IL-23 to the IL-12 receptor b1 colitis found on the surface of CD4 Infliximab › Chimeric IgG1 monoclonal T cells and NK cells antibody › Pharmacokinetics: 45- and 90- › MOA: down-regulation of mg SC injection for PsA and macrophage and T-cell function plaque psoriasis › Pharmacokinetics: IV infusion – Peak plasma concentration = with “induction” = week 0,2,6; 7-13.5 days maintenance every 8 weeks – Elimination half-life = 10-126 – Terminal half-life = 9-12 days days – Elicits human antichimeric › Indications: treatment of adult antibodies = 62% patients with PsA, plaque › Indications: approved for use in psoriasis and Crohn’s disease RA, AS, PsA, Crohn’s disease, › AE: Common: Upper respiratory ulcerative colitis, pediatric tract infection inflammatory bowel disease, and › Rare severe infection, psoriasis malignancy, reversible posterior – granulomatosis with leukoencephalopathy syndrome polyangiitis (Wegener’s SECUKINUMAB › MOA: selectively binds to the IL- granulomatosis), giant cell 17A cytokine, inhibiting its arteritis, Behçet’s disease, interaction with the IL-17A uveitis, and sarcoidosis receptor Adverse Effects › INCREASED infections and › Pharmacokinetics: Available as of TNF-α- macrophage-dependent infection SC injection or lyophilized powder Blocking (including tuberculosis, fungal, for injection Agents and other opportunistic infections) – Elimination half-life = 22-31 › INCREASED risk of HBV days reactivation › Indications: For moderate to › INCREASED risk of skin cancers severe plaque psoriasis › induce the immune system to – Initial loading dose: 300 mg Nonsteroidal Anti-Inflammatory Drugs, Disease-Modifying Antirheumatic Drugs, Nonopioid Analgesics, & Drugs Used in Gout Chapter 36 • Katzung, B. Basic and Clinical Pharmacology SC (0,1,2,3,4 weeks) same subcutaneously for active PsA and moderate – Maximum plasma to severe plaque psoriasis concentration: 3-7 hrs › AE: Common side effect: infection – Absolute bioavailability: 95% – Nasopharyngitis (12%) – Terminal half-life: 4-6 hrs TOFACITINIB › MOA: selectively inhibits all › Indications: treatment of members of the Janus kinase moderately to severely active RA › Therapeutic dose: inhibiting – DOC for CAPS esp neonatal- JAK3 and JAK1 (lesser extent) = onset multisystem interrupt JAK-STAT signalling inflammatory disease pathway (major role in (NOMID) pathogenesis of autoimmune – Effective in gout, Behçet’s diseases) disease, adult onset JIA – JAK1 = controls signal Canakinumab › human IgG1/κ monoclonal transduction from IL-6 and antibody against IL-1β. interferon receptors. › MOA: forms a complex with IL- › Pharmacokinetics: Treatment of 1β, preventing its binding to IL-1 RA = double dose increases receptors response and toxicity › Pharmacokinetics: given by – Oral bioavailability = 74% subcutaneous injection – Elimination half-life = 3 hrs – Peak serum concentration = 7 – Metabolism – 70% in liver days after injection (CYP3A4) – Bioavailability = 66% – 30% excreted unchanged by – Mean terminal half-life – 26 the kidneys days › Indications: prevent solid organ › Indications: active SJIA in allograft rejection children 2 years or older – treatment of inflammatory – Treat CAPS, familial cold bowel disease, autoinflammatory syndrome spondyloarthritis, psoriasis, and Muckle-Wells syndrome and dry eyes Rilonacept › MOA: Neutralizes IL-1β and › AE: increases the risk of infection prevents its attachment to IL-1 › Most common: upper respiratory receptors tract infection and urinary tract › Pharmacokinetics: infection Subcutaneous dose = age- › More serious infections: dependent pneumonia, cellulitis, esophageal › Indications: treat CAPS candidiasis, and other subtypes: familial cold opportunistic infections. autoinflammatory syndrome and › Lymphoma and other Muckle-Wells syndrome in malignancies (lung and breast patients 12 years or older cancer) – reported Adverse Effects › Most common adverse effects - › Other effects: Headache, of Interleukin-1 injection site reactions and upper diarrhea, elevation of liver Inhibitors respiratory tract infections enzymes, and gastrointestinal › Hypersensitivity reactions: perforation Headache, abdominal pain, nausea, diarrhea, arthralgia, and INTERLEUKIN-1 INHIBITORS flu-like illness Important notes › IL-1α plays a major role in the pathogenesis of several GLUCOCORTICOID DRUGS inflammatory and autoimmune Indication › 60–70% of RA patients = effects diseases including RA are prompt and dramatic, capable › IL-1α, IL-1β, and IL-1 receptor of slowing the appearance of new antagonist bone erosions › competitive inhibitor of the › Corticosteroids - serious extra- proinflammatory IL-1α and IL-1β articular manifestations of RA Anakinra › oldest drug; rarely used for RA (pericarditis or eye involvement or › Pharmacokinetics: Given during periods of exacerbation) Nonsteroidal Anti-Inflammatory Drugs, Disease-Modifying Antirheumatic Drugs, Nonopioid Analgesics, & Drugs Used in Gout Chapter 36 • Katzung, B. Basic and Clinical Pharmacology – Other rheumatic diseases in excitement, and disorientation which corticosteroids’ anti- – 15g of acetaminophen = fatal inflammatory effects are – Death = severe hepatotoxicity used: vasculitis, SLE, with centrilobular necrosis Wegener’s granulomatosis, (sometimes = acute renal PA, giant cell arteritis, tubular necrosis) sarcoidosis, and gout › >4 g/d = not usually – Increase in proinflammatory recommended; alcoholism cytokines in the early morning contraindicates = induces morning stiffness › Early symptoms of hepatic and joint paint (circadian damage = nausea, vomiting, rhythm) diarrhea, and abdominal pain Adverse effects › Prolonged use of corticosteroids – › Adverse: Hemolytic anemia and serious and disabling toxic effects methemoglobinemia › Many of adverse effects occur at › Dosage: 325–500 mg four times doses below 7.5 mg daily for acute pain and fever KETOROLAC › Promoted for systemic use = short-term analgesic OTHER › Effective analgesic Acetaminophen › active metabolite of phenacetin = › Replace morphine involving mild responsible for its analgesic effect to moderate postsurgical pain › weak COX-1 and COX-2 inhibitor › Most often given intramuscularly in peripheral tissues or intravenously, oral formulation › no significant anti-inflammatory is available effects › Used with opioid – decrease › Pharmacokinetics: administered opioid requirement (25-50%) orally. › Chronic use = renal toxicity – Peak blood concentrations = TRAMADOL › centrally acting synthetic 30–60 minutes analgesic – Poorly bound to plasma › involve both nonopioid and opioid proteins receptors – Partially metabolized by › No significant anti-inflammatory hepatic microsomal enzymes effects to the inactive sulfate and › Analgesic effect: enhance 5- glucuronide hydroxytryptamine (5-HT) release – <5% = excreted unchanged › Analgesic effect: inhibiting the – N-acetyl-p-benzoquinone reuptake of norepinephrine and 5- (highly reactive metabolite) = HT toxic to both liver and kidney – Half-life = 2- hrs – Unaffected by renal function › Indications: acetaminophen lacks anti-inflammatory properties – does not affect uric acid levels and lacks platelet- inhibiting effects – useful in mild to moderate pain such as headache, myalgia, postpartum pain – Used alone is nadequate therapy for inflammatory conditions such as RA – Preferred for patients allergic to aspirin and in patients with haemophilia, peptic ulcer, and bronchospasm › Adverse effects: Mild reversible increase in hepatic enzymes – Larger doses: dizziness,