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					           Vascular Phase
• Vasodilatation and separation of the cells of the
  vascular endothelium. Leucotrienes appear to
  mediate this response.
• Capillaries are damaged and become
  permeable to plasma proteins causing focal
  edema (swelling).
• Itch and heat and soreness and pain, mediated
  by several powerful endogenous agents.
Function                          Mediators

Increased vascular permeability   Histamine, serotonin, bradykinin,
                                  C3a, C5a, PGE2, LTC4,
of small blood vessels            LTD4, prostacyclins, activated Hageman
                                  factor, high-molecular-weight kininogen
                                  fragments, fibrinopeptides

Vasoconstriction                  TXA2, LTB4, LTC4, LTD4, C5a, N-formyl
                                  peptides

Smooth muscle contraction         C3a, C5a, histamine, LTB4, LTC4, LTD4,
                                  TXA2, serotonin, PAF, bradykinin

Increased endothelial cell        IL-1, TNF-", MCP, endotoxin, LTB4
stickiness

Mast cell degranulation           C5a, C3a
                     INFLAMMATION
                        Trauma

Proteolytic                          Acute Phase Protease
Activation                           Regulatory Activity
                      Biochemical
                       Mediators


                                     Vascular
                       Vascular      Dilatation
        Chemotaxis
                      Permeability


                                                       Systemic
Eicosanoid            Phagocytosis   Cytosis
                                                        Effects
Production


                      Damage by
                      Protease 02           Acute Phase Protease
                                            Inhibitory Activity
            Cellular Phase
• Swelling of damaged vascular endothelium
  and adhesion of platelets.
• CHEMOTAXIS-- leukocytes functioning
  anaerobically infiltrate and release
  lysosomes.
• Sludging of blood (hyperemia, redness) lack
  of adequate microcirculation.
• Decrease O2 tension and hypoxia, tissue
  necrosis ensues.
Function                       Mediators

Phagocytes

Stem cell proliferation        IL-3, G-CSF, GM-CSF, M-CSF

Recruitment from bone marrow   CSFs, IL-1

Adherence/aggregation          iC3b, IgG, fibronectin, lectins

Chemotaxis                     C5a, LTB4, IL-8 and other chemokines,
                               PAF, histamine (for eosinophils), laminin,
                               N-formyl peptides, collagen fragments,
                               lymphocyte-derived chemotactic factor,
                               fibrinopeptides

Lysosomal granule release      C5a, IL-8, PAF, most chemoattractants,
                               phagocytosis
               ARTHRITIS

• Rheumatoid arthritis is an inflammatory
  condition.
• Acute and Chronic phases of
  inflammation.
• Autoimmune in nature.
  – Ab’s produced against IgG
  – (The defective IgG molecules have
    changes in microheterogeneity)
   Adverse Effects of NSAIDs
   • Gastrointestinal tract: gastric irritation, peptic ulcers,
     bleeding, perforation
   • Kidney: decreased renal blood flow, decreased
     creatinine clearance rarely interstitial nephritis or
     nephrotic syndrome
   • CNS: headaches, confusion, tinnitus, aseptic
     meningitis (rare)
   • Hematopoietic system: bleeding, inhibited platelet
     adhesion (irreversible effect with aspirin persisting 10-12
     days)

Page et al. 1997
  ADME/Side Effects of NSAIDs
• The T1/2 of the different NSAIDs vary from short, less
  than 1 hr., to longer than 12 hrs.
• NSAIDs are heavily bound, 60%-90%, to plasma
  proteins.
• NSAIDs are metabolized in the liver in a fashion
  similar to ASA.
• Virtually all NSAIDs can cause dyspepsia and GI
  toxicity including ulceration.
• All except the nonacetylated salycilates can effect
  bleeding time. This is reversible except for aspirin
  which lasts the life of the platelet.
   ADME/Side Effects Continued
• NSAIDs decrease renal blood flow, cause fluid
  retention, and may cause renal failure in some
  patients, particularly the elderly.
• NSAIDs can cause central-nervous-system (CNS)
  effects such as dizziness, anxiety, drowsiness, and
  confusion; these symptoms may occur initially and
  disappear with further use.
• NSAIDs frequently cause small increases in hepatic
  enzyme activity, but life-threatening hepatic toxicity is
  rare.
 Protaglandins are always released
 when cells are damaged and are                   inflammatory stimuli
 detected in increased concentrations         ( heat, mechanical, chemical)
 in inflammatory exudates


                                                         COX-2
            ASA & NSAIDs act here ------->   inducible amounts  markedly
                                                 in response to stimuli



                                                         proteases
                                                     prostaglandin's
Intradermal, intravenous or intra-arterial    other inflammatory mediators
injections of prostaglandins give a
picture reminiscent of inflammation.

                                                      inflammation


   Page et al. 1997
                         arachidonic acid


lipoxygenase                                cyclooxygenase
                     2                  1



leukotrienes                                prostaglandins
                                            thromboxane


phagocyte                                   inflammation
mobilization,
changes in
vascular permeability,
inflammation
                      DMARDs
• PENICILLAMINE (Depen, Cuprimine).
• SULFASALAZINE (Azuifidine).
• GOLD - Gold salts. Gold sodium thiomalate (Myochrysine) and
  aurothioglucose (Solganal) injectable; Auranofin, oral.
• METHOTREXATE (Rheumatrex).
• HYDROXYCHLOROQUINE (Plaquenil).
• AZATHIOPRINE (Imuran).
• CYCLOPHOSPHAMIDE (Cytoxan)


• New treatment models for rheumatoid arthritis
  suggests that more aggressive approaches earlier in
  treatment can avoid or slow the progress of the
  disease.
                  PENICILLAMINE
• Penicillamine is effective in acute, severe rheumatoid
  arthritis in most patients able to tolerate the drug.
• Reductions in joint pain, edema, and stiffness are seen.
• Inhibits T-cell function and antigen presentation.
• Modification of trace metal metabolism and an effect on
  macromolecules could contribute to its efficacy in
  rheumatoid arthritis.
• It is readily absorbed from the gastrointestinal tract and is
  rapidly excreted in the urine, largely as the intact
  molecule.
• Toxicities include Aplastic anemia, thrombocytopenia,
  obliterative bronchitis, polymyositis.
             METHOTREXATE
• This antimetabolite drug, when administered in low
  doses, is effective in the treatment of rheumatoid
  arthritis.
• Decreases PMN chemotaxis, alters DNA synthesis.
• At low doses methotrexate appears to be acting more
  as an antiinflammatory agent than as an
  antimetabolite.
• Dose levels much be watched because of toxicity as
  the drug accumulates. Toxicity includes, hepatic fibrosis,
  acute interstitial pneumonia, bone marrow suppression.
• Toxicity threshold varies form organ to organ with
  bone marrow and GI the most susceptible.
Azathioprine and Cyclophosphamide

• Cyclophosphamide and azathioprine, can reduce
  arthritic signs and symptoms in a significant
  proportion of patients able to tolerate the therapy.
• A reduction in new joint erosions were found in
  patients receiving these agents.
• Interferes with DNA synthesis. Inhibits lymphocyte
  proliferation.
• Side effects associated with the cytostatic-cytotoxic
  drugs severely limit the use of such drugs.
• Twofold increase in non-Hodgkin's lymphoma.
 HYDROXYCHLOROQUINE (Antimalarials)

• The aminoquinolines act on polymorphonuclear
  leukocyte function which may be the key to their
  antiinflammatory activity.
• The 4-aminoquinolines may “stabilize” lysosomal
  membranes reducing the release of destructive
  enzymes in the joints.
• The antimalarials are useful for the treatment of
  rheumatoid disease showing long term antirheumatic
  effects.
                GOLD SALTS
• Gold salts suppress the function of t cells. Inhibit
  PMN function and macrophage activation.
• Gold therapy suppresses the increased phagocytic
  activity that occurs in patients with rheumatoid
  arthritis.
• Aurothiomalate and aurothioglucose are given by
  injection (i.m.) whereas aurafin is orally active.
• Aurothiomalate reduces the numbers of circulating
  lymphocytes and aurafin inhibits the release of PGE2
  from synovial cells and the release of LTB4 and LTC4
  from polymorphonuclear leukocytes.
              Gold Continued
• Gold is difficult to tolerate and can produce significant
  toxicity. Serious reactions occur in 5% of patients.
• The most frequent ADRs with the oral agent aurafin
  are-diarrhea, abdominal pain, neusea, anorexia. With
  all agents pruritus and dermatitis.
• The therapeutic efficacy of gold salts is delayed 4-12
  weeks after initiation of therapy.
Recent Progress in Arthritis Therapy

• New treatment models for rheumatoid arthritis
  suggests that more aggressive approaches earlier in
  treatment can avoid or slow progress of the disease.
• A new class of drugs called leumedins are identified
  that could block the destructive inflammation in
  diseases such as rheumatoid arthritis.
• Recent studies find that the body uses IL-1ra to turn
  off the excessive inflammation typical of some forms
  of arthritis.
                   GOUT
• Gout is an inflammatory reaction to crystals of
  sodium urate.
• Sodium urate is the end product of purine
  metabolism.
• Not everybody who is hyperuric has gout but
  those with gout are hyperuric.
• 3-6.5 mg % in blood - gout pop 6-14 mg %.
• Blood concentration of 6.7 mg % is a
  saturated solution. Less soluble in low
  pH(e.g. joints).
 Two Phases of Gout Treatment
• Treatment of the acute attacks where quick
  relief from painful inflammation is highly
  desirable.
• Long-term lowering of plasma urate
  concentrations.
• For acute attacks: Indomethacin, Colchicine.
• Treatment of chronic hyperuricemia:
  Probenecid, Allopurinol, Sulfinpyrazone
Uric Acid Formation




          Goth’s Pharmacology

				
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