Autocoids

Asthma

ASTHMA:

• PATHOGENESIS: IgE-mediated sensitization of mast cells ------> degranulation of histamine in bronchioles ------> bronchoconstriction and increased secretions.
  • Secreted substances:
    • Histamine
    • Eosinophil and Neutrophil Chemotactic Factors
    • Prostaglandins
    • Leukotrienes
    • Platelet Activating Factor (PAF)
    • Bradykinin Activator



• Central Characteristics:
  • Inflammation is cental to the pathogenesis of asthma. Corticosteroids are needed to fight the inflammation.
  • Bronchial Hyperreactivity
  • Bronchospasm can be treated with bronchodilators, acutely.
• BAD DRUGS:
  • beta-blockers: Don't take beta-blockers with asthma, as it precipitates bronchospasms and attacks.
  • Curare (tubocurarine), morphine: They promote degranulation of mast cells and thus precipitate attacks.
• TREATMENT:
  • MILD ASTHMA:
    • Pre-treat with 1-2 puffs of beta-agonist (as needed).
    • Cromolyn prophylactically, before exposure to allergen or exercise.
  • MODERATE ASTHMA:
    • Inhaled bronchodilators, 3-4X daily, as needed.
    • Prophylaxis with cromolyn or nedocromil.
    • If symptoms persist:
      • Use inhaled steroids.
      • Consider theophylline or oral beta-agonist
  • SEVERE ASTHMA:
    • Inhaled beta-agonists, up to 3-4X daily, as needed.
    • Inhaled steroids, with or without cromolyn and nedocromil.
    • Combination of inhaled steroids + beta-agonists.
    • Consider theophylline and/or oral beta-agonists.

BRONCHODILATORS:

• beta-AGONISTS:
  • MECHANISM: beta₂ adrenoceptors induce higher cAMP ------> bronchiolar relaxation.
    • Stimulate ciliary movements ------> increased mucociliary clearance.
    • Inhibit the release of mediators from mast cells.
  • TOLERANCE: Pharmacologic and physiologic tolerance may occur with prolonged use.
    • Chronic use can lead to increased mortality, as down-regulation of receptors can precipitate refractory asthmatic attacks.
    • IV administration of corticosteroids can up-regulate receptors ------> restore responsiveness one hour.
  • ADVERSE EFFECTS: Side-effects are minimized by local, inhalational administration.
    • Toxicity: Epinephrine toxicity may lead to HTN, CVA's, pulmonary edema, ventricular fibrillation
      • Isoproterenol does not show the same toxicity
    • CV: Tachycardia, arrhythmias.
    • CNS: Dizziness, nervousness.
    • Skeletal muscle tremor
    • Tachyphylaxis
• XANTHINES: Theophylline (PO), Aminophylline (IV)
  • ACTIONS: Main advantage is long duration of action, making it useful in nocturnal asthma. Several secondary proposed mechanisms.
    • Inhibit phosphodiesterase ------> higher cAMP. This is the primary, known mechanism.
    • Blocks adenosine receptors.
    • Moderate broncho-protective effect (against histamine)
    • Modest anti-inflammatory properties
    • Alter immune-cell function.
    • Reduce respiratory muscle fatigue.
  • INDICATIONS:
    • Oral theophylline is good for treating nocturnal asthma.
    • IV aminophylline is used in acute asthma attacks refractory to bronchodilators.
  • PHARMACOKINETICS / DRUG-INTERACTIONS:
    • Theophylline is involved in P-450 metabolism. Agents that increase P450 metabolism (phenobarbitol) can increase theophylline clearance.
    • Smoking increases theophylline clearance
    • Liver disease, heart failure, renal disease decrease theophylline clearance.
  • ADVERSE EFFECTS: It has a narrow therapeutic range, and blood-levels must be monitored.
    • Nausea and Vomiting
    • Toxicity: Concentration over 40 �g / mL. Can lead to seizures.
      • Vomiting (centrally activated) always serves as a premonitory sign of impending toxicity.
    • CV: Arrhythmias, hypotension, cardiac arrest.
• ANTICHOLINERGICS: Ipratropium Bromide is useful for Exercise-induced Asthma
  • PHARMACOKINETICS: Inhaled. It takes effect after 30 minutes and lasts for 4-5 hours.

ANTI-INFLAMMATORIES:

• CORTICOSTEROIDS:
  • ACTIONS:
    • Up-regulate synthesis of lipocortins ------> inhibit Phospholipase A₂ ------> inhibit all arachidonic acid derivatives (esp. prostaglandins, leukotrienes)
    • Beclomethasone up-regulates the receptor density of beta₂-receptors, improving the response to bronchodilators.
  • INDICATIONS:
    • IV corticosteroids are given for status asthmaticus that is refractory to other treatments.
    • Inhaled corticosteroids are used prophylactically, in severe cases of asthma that can't be treated by bronchodilators alone.
  • ADVERSE EFFECTS:
    • INHALED:
      • Soar throat
      • Oral candidiasis
      • Allergic rhinitis
      • Atopic dermatitis
    • SYSTEMIC: Long list.
      • Primary insufficiency (Addison's Disease) upon withdrawal
      • Skeletal: Osteoporosis, cataracts, growth retardation in children.
      • Metabolic: Diabetes, Hypokalemia, Cushing's Syndrome
      • CNS / behavioral affects
      • Susceptibility to infections
• CROMOLYN SODIUM:
  • MECHANISM: It inhibits degranulation of mast cells ------> prevents histamine release.
    • Inhibits Ca⁺²-flux in the cells ------> inhibit degranulation.
  • INDICATION: Prophylactic use only. It has no curative effect on acute asthma attacks.
  • ADVERSE EFFECTS: Mild
    • Airway irritation, dry mouth, cough, perhaps reactive bronchospasm.
    • Rare: skin rashes, eosinophilic pneumonia, allergic granulomatosis.
• ANTI-LEUKOTRIENES: Zileuton, Zafirlukast
  • MECHANISM: They decrease leukotrienes ------> decrease bronchoconstriction, inflammation.
    • Zileuton: 5-Lipoxygenase inhibitor
    • Zafirlukast: Leukotriene-receptor antagonist.
  • INDICATIONS:
    • Exercise Induced Asthma
    • Aspirin-Sensitive Asthma: Asthma precipitated by the shunting of eicosanoids through the leukotriene pathway ------> high leukotrienes.