Mediator Antagonists

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Mediator Antagonists

• By Jim Clarke

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Types of Asthma

• Intrinsic Asthma
• Extrinsic Asthma

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Extrinsic Asthma

• Caused by allergens such as molds, inhaled
  animal protiens, pollens, insect feces, etc.
• Is more typically seen in children young adults
• Airways become sensitive to inhaled chemicals,
  cold air and inert dusts over time

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Characteristics of Extrinsic Asthma

• Induced by outside allergens (spores, molds,
  pollens, etc.)
• Is mediated by IgE and their interactions with
  mast cells
• Degranulated mast cells release powerful chemical
  like prostaglandins leukotrienes
• These chemical cause the inflammatory response

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Intrinsic Asthma

• Inflammatory response in the airway unrelated to
  allergens
• More commonly seen in adults
• Probably caused by activity of T Lymphocytes
• Tends to be chronic and persistent
• Does not respond well to normal treatment methods

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Complexity of Asthma
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Drugs Affecting Inflammatory Mediators

• Cromolyn sodium (Intal)
• Nedocromil sodium (Tilade)
• Zafirlukast (Accolate)
• Zileuton (Zyflo)
• Montelukast sodium (Singulair)

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Cromolyn (Intal)

• Used to prevent asthma attacks
• referred to as a controller
• Used to prevent exercise-induced bronchospasm
• Available in a nasal spray as eye drops along
  with the inhaled form

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How Cromolyn Works
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How Cromolyn Works

• Blocks the effects of antibodies on Mast Cells
  thereby preventing the release of chemical
  mediators
• Once mediators are released it has a limited
  effect
• Tends to work only in intrinsic (allergic) asthma

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How is Cromolyn Available?

• As a dry-powder (via Spinhaler)
• Not widely used since it can be irritating to the
  airway
• Requires high inspiratory flowrates
• Now available as a liquid solution for HHN
• 20 mg/ 2 ml (1 strength) - qid
• Comes available as an MDI - 2 puffs, qid

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Side Effects of Cromolyn

• Mild side effects - nausea, nervousness, cough,
  wheezing, nasal itching burning

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Nedocromil (Tilade)

• Indications are the same as with Cromolyn
• Must be used on a regular basis in order to be
  effective!
• Is a controller, not a reliever

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Mode of Action of Tilade

• Inhibits the activity of inflammatory cells
• Mast cells eosinophils cytokines airway
  epithelial cells
• Appears to be work better in adults than Cromolyn

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Available Forms of Tilade

• Only currently available in MDI form
• 1.75 mg per actuation given 2 puffs QID

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Side Effects of Tilade

• Very well tolerated by most patients
• Some effects are unpleasant taste, headache
  nausea

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Zafirlukast (Accolate)

• Only available in tablet form for use in those gt
  12 years of age
• Given bid
• Used to prevent asthma and to treat chronic asthma

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Mode of Action of Accolate

• Prevents the inflammatory response of asthma by
  blocking the receptor site for leukotrienes
• Blocks asthma inflammation due to cold air,
  exercise, allergens and aspirin
• Generally is a less preferred alternative to
  steroids for asthma prevention treatment

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Arachadonic Acid Pathway for Leukotriene
Production
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Side Effects of Accolate

• Headache
• Nausea
• Diarrhea
• Generalized abdominal pain

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Zileuton (Zyflo)

• Available in tablet form only
• Indications are the same as for Accolate

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Mode of Action of Zyflo

• Inhibits the metabolic pathway responsible for
  the production of leukotrienes from arachadonic
  acid

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Side Effects of Zyflo

• Headache
• General pain /or abdominal pain
• Dyspepsia
• Liver enzyme elevation
• Zyflo interacts with Theophylline preparations
  causing theophylline levels to rise

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Montelukast (Singulair)

• Acts in a similar fashion to Zafirlukast
• Main advantage is that it is taken once a day for
  asthma prevention!

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Aerosolized Antiinfective Agents

• Pentamidene (NebuPent)
• Ribavirin (Virazole)

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Indications for Use of Pentamidine

• Used in aerosol form and systemically in the
  treatment and prevention of Pneumocystis Carinii
  Pneumonia (PCP)

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Rationale for Aerosol Administration

• PCP is located in the alveolar regions of the
  lung where aerosolized forms can be targeted
• Parenteral forms of Pentamidine can cause
  numerous side-effects

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Common Side Effects of Pentamidine Via Aerosol

• Cough airway irritation
• Shortness of Breath
• Bad taste
• Bronchospasm Wheezing

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Aerosol Dose of Pentamidine

• 300 mg of dry powder mixed in 6 ml of saline
• Given once a week for 4 weeks
• Less widely used since the development of an oral
  drug dosing protocol was advocated by the CDC in
  1992

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Respirgard Nebulizer for Pentamidine
Administration
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Ribavirin (Virazole)

• Anti-viral agent used primarily for treatment of
  Respiratory Synctial Virus (RSV) in newborns and
  children
• Has been used for treatment of herpes simplex
  influenza viruses on occasion
• Given in aerosol form only

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Indications for Virazole Use

• To treat severe forms of RSV that have caused
  bronchiolitis or pneumonia
• Generally only used unless disease progresses to
  a severe form with patient presenting with severe
  hypoxemia
• Can be given via head-hood or in-line with
  mechanical ventilator

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Aerosol Administration Issues

• Available in 6 grams of dry powder
• Powder is diluted in enough water to make 300 ml
  of solution
• Given via nebulizer over 12 to 18 hours/day
• Must be given via a SPAG nebulizer
• Small Particle Aerosol Generator
• See next slide for picture of unit

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SPAG Nebulizer for Virazole Administration
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Environmental Issues

• Health care workers should minimize exposure to
  Virazole due its reported mutagenic effects
• Cases of conjunctivitis have been reported in
  health care providers exposed to aerosol
• Pregnant females should avoid exposure

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Aerosolized Antibiotics

• Have been used in the prevention treatment of
  pneumonia in Cystic Fibrosis patients
• Works best on gram negative organisms
• Pseudomonas aeruginosa
• Hemophilus influenza OR
• Staphylococcus aureus

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Types of Antibiotics Used

• Gentamicin
• Tobramycin
• Carbencillan
• Colomycin

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Clinical Uses in CF

• To maintain present lung function or reduce rate
  of deterioration
• To treat or prevent lung colonization by
  Pseudomonas aurginosa
• To treat severe respiratory infections

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Thats All Folks!