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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