Pharmacolgy of Autocoids in Inflammation and Autoimmune Diseases

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Pharmacolgy of Autocoids in Inflammation and
Autoimmune Diseases

• Keith W. Crawford, R.Ph., Ph.D.
• Department of Pharmacology
• Howard University College of Medicine

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Vascular Changes in Inflammation

• Mediators of blood flow and vascular permeability
  changes
• vasoactive amines (histamine, serotonin)
• vasoactive peptides (bradykinin)
• vasoactive lipids (prostaglandins, leukotrienes)
• Mediators of leukocyte chemotaxis
• leukotriene B4
• Eosinophil chemotactic factor of anaphylaxis

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Tissue damage in Inflammation and Autoimmune
Disease

• Generation of reactive oxygen species (O2-, H2O2,
  HOCl) and proteolytic enzymes (collagenases,
  elastase) by phagocytic cells
• Cytotoxic complement proteins
• Cell- mediated and humeral immune responses
• Release of pro-inflammatory cytokines

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Modulators of Mast Cell histamine Release

• Agents targeting IgE
• Omalizumab (Xolair) a monoclonal antibody
  directed at FceRI, the receptor for
  allergen-bound IgE on mast cells and basophils
  that mediates histamine release. Histamine
  release is blocked and surface FceRI receptors
  are down-regulated. Given S.C. for allergic
  asthma.

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Modulators of Mast Cell histamine Release

• Inhibitors of Mast cell degranulation
• These agents appear to reduce intracellular
  calcium by acting at channels (Ca 2, Cl-??)
  resulting in decreased histamine release and
  leukotriene synthesis. May also inhibt moncyte
  and eosinophil chemotaxis.
• -Cromolyn sodium (Intal)- inhaled for the
  prophalaxix of allergic asthma OTC for allergic
  rhinitis
• -Nedocromil sodium (Tilade) inhale for allergic
  astma, ophthalmic solution for allergic
  conjunctivitis

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Histamine 3 known receptor typesH1, H2
targets for therapeutic agents

• H1 receptor coupled to Gq, initiate
  phosphoinositide turnover and production of IP3
  and diacyglygerol
• H2 receptor coupled to Gs, increases adenylate
  cyclase actvity and cAMP production

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Physiologic effects of histamine

• Smooth Muscle
• Vascular
• Bronchiolar
• Gut
• Cutaneous effects
• Secretory Epithelia
• GI

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Therapeutic Classes

• No clinical use for H1 agonist
• H2 agonists used in diagnostic tests measuring
  gastric secretory activity
• H1 antagonists have a number of clinical uses
• H2 antagonists used to treat various GI disorders

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First vs. Second Generation H1 antagonists

• Many first generation H1 antagonists interact
  with other receptor types
• diphenhydramine muscarinic receptors
• Promethazine dopamine, muscarinic, a1
• Cyproheptadine serotonergic receptors
• Second Generation H1 antagonists are
• highly selective for H1 receptors
• do not penetrate the blood-brain barrier less
  sedation
• Have long half-lives
• Are primarily indicated for allergic rhinitis

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Some Uses for H1 antagonists

• Allergic rhinitis e.g.chlorpheniramine,
  loratidine
• Motion sickness eg. meclizine, chlorcyclizine
• Hypnotic agents e.g.doxylamaine,
  diphenhydramine
• Pruritis e.g. hydroxyzine
• Serum sickness- e.g. promethazine
• Anti-emetics- e.g. promethazine
• Antitussive e.g. diphenhydramine
• Carcinoid tumors (serotonin-mediated)
  cyproheptadine
• Allergic conjuctivitis e.g. levocobastine

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Clinical uses for H2 receptor Antagonists

• Gastric and duodenal ulcers
• Gastroesophageal reflux
• Erosive esophagitis
• Heartburn (available OTC)

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The Immune System in Inflammation/Autoimmune
Disease

• Lymphocyte infiltration of inflammed tissues
• Production of inflammatory cytokines

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Cytokine Modulators in Inflammatory/Autoimmune
Disease

• Tumor Nerosis factor-alpha (TNF-a )
• -Infliximab (Remacaide) a chimaeric
  monoclonoal againt TNF. Indicated for Crohns
  Disease. RA, possibly Psoriasis
• -Etanercept (Enbrel)- a soluble dimeric
  TNF-receptor fusion protein that binds TNF-a and
  ß. Indicated for RA, possibly psoriasis
• Interleukin-1 (IL-1)
• -Ankinra (Kineret)- Human IL-1 antagonist
  differs from the native IL-1 antagonist by having
  a methionine in the amino terminal position.
  Administered subcutaneously for the treatment of
  RA.
  

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Alefacept (Amevive)

• A fusion protein composed of the extracellular
  CD2 binding portion of human leucocyte function
  antigen-3 (LFA-3)
• LFA-3 is expressed on the surface of APC and
  associates with CD2 on lymphocytes leading to
  T-cell activation. Alefacept therefore blocks
  T-cell activation.
• The drug is indicated for treating Psoriasis

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Lipid Autocoids
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Thromboxane vs. Prostacyclin

• Thromboxane (platelet) promotes platelet
  aggregation prostacyclin (endothelium) inhibits
  platelet aggregation. Question Why is low-dose
  aspirin such a potent antiplatelet agent?
• Thromboxane is a brochoconstrictor Prostacyclin
  is a brochodilator.
• Thromboxane is a vasoconstrictor Prostacyclin is
  a vasodilator

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Prostaglandins (PGE2) and Inflammatory pain
sensitization

• PGE2 has recently been shown to inhibit a glycine
  receptor (GlyR alpha3) in its action regulating
  central inflammatory pain sensation.
• GlyR alpha3 is expressed in the superficial
  layers of the spinal cord dorsal horn.

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Indications for Prostaglandin analogues

• Alprostadil- maintains a patent ductus arteriosus
  in the fetus useful in treating erectile
  dysfunction
• Misoprostil a PGE2 analogue used to treat
  NSAID-induced gastritis
• Carboprost Dinoprostone abortafacients, may be
  used to induce labor
• Lantanoprost used in treating glaucoma

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Aspirin (Acetyl Salicylic Acid)

• Irreversibly acetylates cyclooxygenase
  permanently disabling the enzyme
• Salicylate moiety competitively inhibits
  cyclooxygenase
• Aspirin displays dose-dependent kinetics
• Signs and symptoms of salicylate toxicity
• Dosing of aspirin differs greatly depending on
  the indication

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