Mediator Antagonists

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Mediator Antagonists

• Chapter 12

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Mechanisms of inflammation in asthma

• Types of asthma
• Extrinsic dependent on allergies
• Intrinsic shows no sensitization to allergens
• With both forms airway inflammation is evident
  causing bronchoconstriction, airway swelling,
  mucus secretion and obstruction

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Allergic response

• Primarily involves mast cells and immunoglobin E
• Lymphocytes (T cells) activated by an antigen
  result in the production of IgE
• IgE binds to mast cells
• Releases mediators of inflammation such as
  prostaglandins, leukotrienes, histamine, platelet
  aggregating factor, and cytokines

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Allergic response

• Mediators from mast cell cause vascular leakage,
  bronchoconstriction, mucus secretion, and mucosal
  swelling
• Once initiated the inflammatory response causes
  the release of eosinophils, neutrophils, and
  lymphocytes which increase the severity of the
  inflammation

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Disodium cromoglycate/Cromolyn sodium

• Comes from the seeds of a plant Ammi visagna
• Extract of khellin taken from here-originally
  used to treat colic
• Prophylactic agent to prevent asthmatic reactions
• Not related to any other drug category such as
  beta agonists, xanthines, or glucocorticoids

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Indications for use

• Prophylactic management of asthma
• Prevention of exercise induced asthma
• For allergic rhinitis
• Extrinsic asthma

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Mode of action

• Prevents mast cell degranulation
• Blocks release of chemical mediators
• Must be used as a pretreatment
• May work by preventing calcium from allowing the
  contraction of the filaments on the mast cell
  which release the mediators
• Does not work as an antagonist on the mediators
  themselves
• Does not affect alpha or beta receptors

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Mode of action cont.

• Does not prevent antibody formation, the
  attachment of IgE, and the combination of
  antibody-antigen reactions-only prevents the
  release of the mediators

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Dosage and administration

• Spinhaler (dry powder inhaler)-can be irritating
  and cause coughing or bronchoconstriction. May
  need beta 2 agonist prior to or after tx.
• Ampule for nebulization (20 mg/2ml). Brand names
  Aarane or Intal
• MDI
• Nasal solution(Nasalcrom)

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Side Effects

• Safe drug
• Dry powder causes throat irritation, hoarseness,
  dry mouth
• Nebulizers associated with cough, wheezing,
  sneezing

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Clinical Applications

• Drug is only prophylactic and should not be used
  during acute bronchospasm. No bronchodilating
  action.
• No affect on the adrenal system and cant be used
  as replacement for corticosteroids
• May take 2 to 4 weeks for improvement in
  patients symptoms

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Nedocromil sodium (Tilade)

• Cromolyn sodium type drug
• Prophylactic therapy for asthma management
• Inhibits mast cell mediator release
• Can inhibit eosinophil activity

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Leukotrienes

• Production from leukocytes.
• Release of leukotrienes during inflammatory
  reaction causes narrowed airways, excessive mucus
  production, airway inflammation

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Role of leukotrienes in asthma

• Leukotrienes originally called SRSA
• Released by inflammatory cells
• Directly contract airway smooth muscle
• 1000 x more potent than histamine in causing
  bronchial contraction and the contraction lasts
  longer
• Also stimulate hypersecretion of mucus

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Leukotrienes

• Also stimulate vascular permeability which causes
  airway swelling

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Antileukotriene therapy

• Inhibit the production and block the action of
  leukotrienes
• Two main classes leukotriene synthesis
  inhibitors and leukotriene receptor antagonists

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Pharmacologic agents

• Montelukast (singulair)
• Leukotriene receptor antagonist
• Blocks leukotrienes at receptor site
• Improves airway obstruction, may keep episodes
  from worsening in chronic asthma

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Pharmacologic agents

• Zafirlukast (Accolate)
• Receptor antagonist used in the tx of chronic
  asthma
• Inhibits bronchoconstriction.

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Pharmacologic agents

• Zileuton (Zyflo)Inhibits formation of
  leukotrienes
• Inhibits bronchoconstriction caused by various
  allergens

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Side effects

• Accolate(Zafirlukast)-headache, nausea, diarrhea,
  abdominal pain, infection
• Zileuton(Zyflo)-headache, abdominal pain, loss of
  strength, stomach upset
• Montelukast(Singulair)- does not have these side
  effects

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