ACETAMINOPHEN

Active metabolite of phenacetinWeak COX-I and COX-2 inhibitorNo significant anti-inflammatory effects

Pharmacokinetics:Peak blood level is reached in 30-60 minMetabolized by hepatic microsomal enzymes

and form acetaminophen sulfate and glucronide

N-acetyl-p-benzo-quinoneimine (NAPQI)-Toxic to liver and kidneys

Indications

325 – 1000mg (total dose not > 4000mg)Headache, myalgia, postpartum painIn rheumatoid arthritis with anti-

inflammatory agentPreferred to aspirin in peptic ulcer, in

children with viral infections

Adverse effects

Mild increase in hepatic enzymesDizziness, excitement & disorientation at

larger dosesDose greater than 4-6 g/d is not

recommended - cause liver damage15-20gm potentially fatal (30tablets)

Mechanism of hepatotoxicity of acetaminophen

NAP reacts with sulfhydryl gps in GSH normally & then excreted as mercapturic acid in urine but in toxic dose GSH is depleted and toxic metabolite accumulates

Treatment Supportive therapyN-Acetylcysteine

COX-2 SELECTIVE INHIBITORS

Celecoxib, rofecoxib, valdecoxib, parecoxib, etoricoxib, lumaricixib

Inhibit prostaglandin synthesis by the COX-2 isozyme

Analgesic, antipyretic and anti inflammatory effects

No effect on platelet aggregationNo cardioprotective effect

CELECOXIB

Highly selective COX- 2 inhibitor. Half life is 11 hrs Metabolized mainly in the liver Effective in rheumatoid arthritis and

osteoarthritis. Less production of peptic ulcer Inhibit COX 2 mediated prostacyclin

synthesis in vascular endothelium- platelet aggregation

DMARDS

Disease Modifying Anti-Rheumatic Drugs

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SLOW ACTING

ANTI-RHEUMATIC

DRUGS

orSAARDs

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RHEUMATOID ARTHRITIS9

An immunologic diseaseSynovial inflammation leading to cartilage

damage and bone erosions and subsequent changes in joint integrity is the hallmark of the disease

Persistent, symmetrical peripheral arthropathyPresentation: swollen, painful, stiff hands &

feetTreatments that arrest 0r slow progression by

modifying disease itself

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Mechanism of Action of DMARDs

diverse group of drugs with different & poorly understood mechanisms of actions

slow the bone damage associated with RA & affect more basic inflammatory mechanism than the NSAIDs

effects of DMARDs may take 6 wks to 6 months to become evident

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Non-biologic DMARDsNon-biologic DMARDs Biologic DMARDsBiologic DMARDsMethotrexateAzathioprineCyclophosphamideChloroquine &

hydroxychloroquineCyclosporineLeflunomideMycophenolate mofetilSulfasalazine D-PenicillamineGold Salts

AbataceptRituximabTocilizumabTNF-α blocking

drugs- Adalimumab- Etanercep- Infliximab Immunoabsorption

apheresis

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DRUGS

METHOTREXATE

First DMARD of choice Used at much lower doses than those

needed in cancer chemotherapy

MOAAt lower doses it inhibits aminoimidazole-carboxamide ribonucleotide (AICAR-inhibits AMP deaminase) transformylase & thymidylate synthetase that accounts for the suppression of the immunologic mechanisms underlying rheumatoid arthritis

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Pharmacokinetics

70% absorbed after oral administrationMetabolized to less active metaboliteExcreted principally in the urine, but upto 30%

may be excreted in bileConcentration may increase in presence of

hydrochloroquine-reduces clearance or tubular secretion

Other Clinical uses (15-25mg weekly)

juvenile chronic arthritispsoriatic arthritis

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Adverse effects

NauseaMucosal ulcersLeukopenia, alopecia, stomatitis, GI ulceration Progressive dose-related hepatotoxicity

ContraindicationsPregnancy

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AZATHIOPRINE

Synthetic DMARD

MOA Acts through metabolite 6-thioguanine Suppresses inosinic acid (IMP)

synthesis, B & T-cell function, IL-2 secretion & immunoglobin production

Production of 6-thioguanine is dependent on thiopurine methyltransferase (TMPT)

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Adverse effects19

Bone marrow suppressionGI disturbancesInfection riskLymphomaAllergic rash & hepatotoxicity rarely

CYCLOPHOSPHAMIDE

Synthetic DMARDMajor metabolite phosphoramide

mustard cross links DNA to prevent cell replication

MOASuppresses T cell & B cell function by 30-40%T cell suppression is responsible for clinical response in RA

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Adverse effects

Dose related infertility in both sexes

Bone marrow suppression

Alopecia, hemorrhagic cystitis

DOSE: orally 2mg/kg/dRA, SLE, vasculitis

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CHLOROQUINE22

& hydroxychloroquineSupress T-lymphocyte responses to

mitogensDecreased leukocyte chemotaxisStabilizing of lysosomal enzymesInhibition of DNA & RNA synyhesisTrapping of free radicalDOSE: 200mg/d

CYCLOSPORINE

A peptide antibioticNon-biologic DMARDInhibits IL-1 & 2 production through gene

regulationInhibiting macrophage-T cell interactionMetabolized by CYP3A4Leukopenia, thrombocytopeniaCardiac toxicity, bladder cancerSterility

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LEFLUNOMIDE24

Nonbiologic DMARDInhibits T-cell proliferation by inhibiting

RNA synthesis (pyrimidine synthesis)Inhibits T-cell proliferation & production of

autoantibodies by B-cellsInhibits bony damageAs effective as methotrexateDiarrhea (25% pts)Mild alopecia, weight gain & increased BP

SULFASALAZINE

Metabolized to sulfapyridine & 5-aminosalicylic acid

IgA & IgM RF reducedSupression of T-cell response & inhibition

of B-cell proliferationInhibits release of inflammatory cytokinesReduces radiologic disease progressionNausea, vomiting, headache, rashNeutropenia, hemolytic anemia,

methhemoglobinemia, pulmonary toxicity

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GOLD

MOAalters the morphology & functional capabilities of human macrophages

I/M formulations: aurothiomalate & aurothioglucose

Oral formulations: auranofin

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Adverse effects

pruritic skin rashes with eosinphilia stomatitis, metallic taste hematologic abnormalities proteinuria , nephrotic syndrome

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RITUXIMAB28

Biologic DMARD-Chimeric monoclonal antibodyTargets B lymphocyte through cytotoxicity &

apoptosisDepletion of B lymphocytes decreases

inflammation by decreasing presentation of antigens to T lymphocytes & inhibiting secretion of proinflammatory cytokines

IV infusions 1000mg 2 weeks apart repeated 6-9 mths

Infusion reactions (pretreatment with glucocorticoids)

ABATACEPT

Biologic DMARD-T-cell costimulation blockerInhibits activation of T-cellsMonthly infusion after induction at 0, 2 & 4 wkReduces clinical signs & symptoms of RA

including slowing of radiographic progressionSlightly increased risk of infections (should not

be used in combination with TNF- antagonists)Possible increase in lymphomas

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TNF-α blocking drugs

Biologic DMARDsAnti-TNF antibodies inhibit T cell & macrophage function, & subsequently interfering with TNF-α

Adalimumab Infliximab Etanercept

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Adverse effects

Increased risk of bacterial infectionsOpportunistic infectionsIncreased risk of macrophage-

dependent infections (TB)- screening of latent or active TB

Lymphoma risk

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Thank You!

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