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					Strategies of Anti-Inflammatory Therapy:

       Target a single mediator – antihistamines and leukotriene modifiers
            i. Antihistamines: H1 – inverse agonists / comp antagonists
                   1. H1 – Old: Diphenhydramine & Chlorpheniramine
                   2. H1 – New: Cetrizine / Loratadine / Fexofenadine
           ii. Leukotriene antagonists to CysLTR1 :
                   1. Zafirlukast
                   2. Montelukast – better b/c no meal restrictions
       Target multiple mediators – anti-inflammatory steroids, NSAIDs (shot-gun approach)
            i. COX pathway
                   1. Aspirin – irreversibly inhibits COX
                   2. tNSAIDs – non-selective COX inhibitor
                         a. Ibuprofen – less GI SE than Aspirin
                         b. Naproxen
                         c. Diflunisal
                         d. Ketoprofen
                         e. Indomethacin – MOST POTENT
                         f. Sulindac
                         g. Piroxicam  bad GI bleed
                   3. Selective COX2 inhibitors – Celecoxib
                   4. Acetominophen – Tylenol – FEVER AND PAIN!
       Stop mediator production – synthesis inhibitors
            i. LTs – 5-LO inhibitor: Zileuton
       Stop mediator release
       Stop mediator action – antagonists or inverse agonists
            i. Kinin receptor antagonist: Icatibant – for C1 inhibitor def

       Cortisol is an anti-inflammatory!
       Synthetic steroids: bethamethasone, dexamethasone, methylprednisone, predinisone
       Calcineurin inibs – post organ transplant – both block DEPHOSPHORYLATION needed for cytokine GENE
        EXPRESSION & T cell activation
            o Cyclosporine to cyclphilin
            o Tacroliums to FKBP
       Antiproliverative/antimetabolic drugs
            o Sirolimus: INHIBITS ENZYME NEEDED FOR CELL PROLIFERATION of T cell. – cell cycle
            o M. mofetil: INHIBITS IMPDH needed for de novo guanine synthesis
            o Other anticancer drugs: azatioprine, methotrexate, cyclophosphamide
       Abs:
            o Muromonab-CD3 – blocks CD3 on TCR
            o Daclizumab or Basiliximab bind to IL-2 receptor
Anti-inflammatory & Immunosuppressive Drugs (Regal)

 (1)    Inflammation is a process: Sublethal injury  Mediators  Inflammation (redness, swelling, heat, pain)
              Injury d/t: heat, mechanical, chemical, bacteria, virus, Ab-Ag reactions
              Mediators: endogenous substances (autacoids/local hormones) that are stored or rapidly
               synthesized, intended to act only at the site of injury. Lots of redundancy!

Fever    Pain (either causes    Redness & heat          Swelling (        Chemotaxis          Airway           Hypotension
        pain or reduces pain     (vasodilation)        permeability)                         constriction
                                   Histamine             Histamine                             Histamine         Histamine
PGEs            PGE₂                  PGE₂                Peptido-           Peptido-           Peptido-
                                                     leukotrienes (LTC₄,   leukotrienes       leukotrienes
                                                         LTD₄, LTE₄)       (eosinohpils)   (LTC₄, LTD₄, LTE₄)
         PGI₂ - prostacyclin   PGI₂ - prostacyclin                             LTB₄               PGD₂
               Kinins                Kinins                Kinins                               Kinins            Kinins

 (2)    Acute inflammation review:
             Changes in blood vessel caliber & flow : arteriolar dilation, increased blood flow, slowing of flow to
                stasis. This causes redness & heat.
             Increased vascular permeability : post capillary venules leak large molecules, contraction of
                endothelium w/ spaces in bxt. This causes swelling which can lead to pain.
             Leukocytic infiltration : post capillary venules, pavementing of leukocytes, mvmt into
                extravascular space, chemotaxis
             Mediators that will cause all this to occur: Histamine, Prostaglandins, Leukotrienes, Platelet
                Activating Factor (PAF), kinins, products of complement system activation, cytokines, chemokines,
                interleukins, adhesion molecules.
                      i. Mediators in any given situation will differ depending on: nature and extent of injury,
                         location of injury, type of Ag-Ab rxn
             Airway constriction (bronchoconstriction) is relevant in asthma (immune mediated lung disease)
             Hypotension is relevant in shock (systemic release of inflammatory mediators). Can be d/t
                widespread vasodilation, increased capillary permeability & fluid loss from circulation!
 (3)    Strategies of Anti-Inflammatory Therapy:
             Target a single mediator – antihistamines and leukotriene modifiers
             Target multiple mediators – anti-inflammatory steroids, NSAIDs (shot-gun approach)
             Stop mediator production – synthesis inhibitors
             Stop mediator release
             Stop mediator action – antagonists or inverse agonists

(1)   Immunosuppressive drugs are used to dampen the immune system in organ transplantation,
      autoimmune disease & hypersensitivity. Works best on primary immune response. Will work better if
      therapy starts before exposure to immunogen. Want to do this so you don’t get immune mediated tissue
      damage which thereby means you don’t have an inflammatory response related to the tissue damage.
(2)   Limitations include:  risk of all infections and lymphomas & related malignancies
(3)   Major classes of immunosuppressive drugs:
           Glucocoriticoids = Anti-inflammatory steroids. Made by adrenal cortex. Cortisol turns off
              immune system as a negative feedback inhibitor = natural anti-inflammatory system.
                   i. Corticosteroids (21C) are released in response to stimulation by ACTH.
                          1. Mineralocorticoids (electrolyte balance)
                          2. Glucocotriocoids (carbohydrate metabolism)

      Activity:           Prototype          Sodium Retention         Liver Glycogen       Anti-Inflammatory
                          Compound         (can the steroid  Na    Deposition (can the
                                           excretion by kidney?)   steroid cause hepatic
                                                                       deposition of
 Mineralocorticoids      Aldosterone                +                        -                    -
  Glucocorticoids          Cortisol                 -                        +                    +

                   ii. Androgens (19C)
                           1. NOT body building
                  iii. Why do we use anti-inflammatory steroid drugs?? When immune system is too active,
                       the addition of exogenous glucocorticoids can turn it off (endogenous ones are doing
                       their job). Want to minimize drug action on the mineralocorticoid receptor.
                           1. Synthetic steroids: Betamethasone, Dexamethasone, Methylprednisone,
                           2. Oral, parenteral & topical administration. Some systemic absorption always
                                occurs. Metabolized by liver & excreted by kidney.
                           3. Inhaled glucocorticoids are designed for uptake & prolonged tissue binding in
                           4. How do steroids work?? Time lag in steroid action. There are a number of
                                protein products responsible for immunosuppressive effects. Steroid GR complex
                                interacts w/ TFs which can repress gene expression.
                  iv. Effects of glucocorticoids on ppl:
                           1. Effects on cell mvmt
                                    a. Neutrophils – more of them, release from BM , in circulation longer,
                                        blockage of migration to inflammatory sites by  adherence
                                    b. Lymphocytes – lymphopenia, cells not lysed, but move to extravascular
                                    c. Monocytes & eosinohpils are decreased in peripheral blood
                           2. Effects on synthesis &/or release of inflammatory mediators
                                    a. Reduced expression of COX2
                                    b. Inhibits release of arachidonic acid from PLs =  PG & LT production
                        c. Inhibits degranulation of mast cells and basophils
                        d. Inhibits synthesis & release of TNF, IL1, IL2 and IFN
         v. Therapy:
                 1. W/ systemic admin  SE can be life threatening
                 2. Cortisol & analogs prevent / suppress R, S, H P…but underlying cause of disease
                 3. Lowers host resistance to microbial and fungal infection.
        vi. Therapeutic principles:
                 1. Dosing often by trial & error
                 2. Single dose OK; a few days OK as long as not high dose…prolonged = BAD!
                          a. also…don’t just take someone off a long dose, need to TAPER
       vii. Uses:
                 1. Arthritis
                 2. Rheumatic carditis
                 3. Renal diseases - SLE nephrotic syndrome
                 4. Collagen diseases - systemic lupus
                 5. Allergic diseases - not acute anaphylaxis
                 6. Bronchial asthma - inhalation, systemically
                 7. Ocular diseases - in bacterial, fungal or viral infection, glucocorticoids can mask
                     the progression of the disease
                 8. Skin diseases – eczema
                 9. Diseases of the intestinal tract - chronic ulcerative colitis
                 10. Malignancies
                 11. Diseases of the liver
                 12. Shock - use is controversial
   Calcinerin inhibitors – in immunosuppression after organ transplantation
          i. Cyclosporine: binds to cytoplasmic receptor protein called cyclophilin  inhibiting
             caclineurin activity. Blocks dephosphorylation events needed for cytokine gene
             expression & T cell activation.
                 1. Met in liver
                 2. Lots of drug interactions
                 3. Long term tx for transplantation
                 4. Renal toxicity – BAD SE
         ii. Tacrolimus (FK506): binds to cytoplasmic receptor called FKBP  inhibition of calcineurin.
             Blocks same stuff
                 1. 100 times more potent than cyclosporine
                 2. Toxicity similar nephrotoxicity
   Antiproliferative/antimetabolic drugs – prevent clonal expansion of both B & T cells
          i. Sirolimus (rapamycin): binds to FKBP to inhibit enzyme needed for cell
             cycle proliferation – blocks G1  S in IL driven T cell proliferation.
                 1. Toxicity: WORSE than Aspirin!
        ii. Mycophenolate mofetil: a metabolite is an inhibitor of inosine
             monophosphate dehydrogenase (IMPDH), an imp enzyme in the de
             novo pathway of guanine nt syn. B & T cells are highly dependent on
             de novo synthesis of purines for cell proliferation, while other cells can
             use salvage pathways.
                iii. Other anticancer drugs like azathioprine, methotrexate & cyclophosphamide
                         1. Immune cells prolif in response to a specific Ag, Ca cells just go nuts. Low doses
                              block immunoproliferation & high dose will kill cancer cells. DOSING
            Antibodies
                  i. Eliminate lymphocytes
                         1. Anti-thymocyte globulin: purified Igs. Will bind to thymocytes in circulation 
                              lymphopenia & impaired T cell immune response
                                   a. Toxicity: Ig being seen as foreign  serum sickness & nephritis
                 ii. Affect T cell function
                         1. Muromonab-CD3 (for kidney, liver and heart transplants)
                                   a. Ab binds to CD3, TCR can’t work. Can cause cytokine release syndrome:
                                            i. Flu-like sx  life-threatening shock. Crosslinking = cytokine
                         2. Daclizumab or Basiliximab (organ transplantation)
                                   a. Mouse Ab to IL-2 receptor
                                   b. Bind to IL-2 receptor on activated but not resting T cells and block IL-2
                                      mediated T cell activation
                                   c. Anaphylaxis can occur. No cytokine release syndrome

                  Site of Action of Selected Immunosuppressive Agents on T Cell Activation

             DRUG                                    SITE OF ACTION

Glucocorticoids                  Glucocorticoid response elements in DNA (regulate gene transcription)

Cyclosporine                     Calcineurin (inhibits phosphatase activity)

Tacrolimus                       Calcineurin (inhibits phosphatase activity)

Sirolimus                        Protein kinase involved in cell-cycle progression (mTOR) (inhibits activity)

Mycophenolate mofetil            Inosine monophosphate dehydrogenase (inhibits activity)

Muromonab-CD3 (Ab)               T-cell receptor complex (blocks antigen recognition)

Daclizumab, Basiliximab (Ab)     IL-2 receptor (block IL-2-mediated T-cell activation)

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