Muscarinic Antagonists

• Mechanism of Action:
  • muscarinic cholinergic receptor activation promotes:
    •  contraction of airway smooth muscle
    •  increased mucous secretion
  • Antimuscarinic drugs block vagus nerve-mediated acetylcholine effects on airway smooth muscle muscarinic receptors

• Antimuscarinic drugs are only capable of preventing the cholinergic-mediated component of bronchospasm;
  • other components may contribute significantly to the bronchospastic response
  • the extent of the cholinergic-mediated bronchospastic component probably varies between patients

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Clinical Use:-- Antimuscarinic Drugs

• Effective bronchodilators
  • Preferred route of administration (enhanced organ selectivity): inhalation
• Antimuscarinic with limited systemic adverse effects: ipratropium bromide (Atrovent) (quaternary nitrogen, permanently charged)
  • ipratropium bromide available in combination with albuterol (Combivent)

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• Antimuscarinic drugs- Clinical Findings:
  1. valuable even in partial-responders
  2.  valuable inpatients intolerant of inhaled beta-agonist drugs
  3. may be slightly less effective than beta-agonist drugs in reversing bronchospasm
  4. probably equally effective for patients with COPD (that includes a partially reversible element)
  5. Role in acute severe asthma:
     • enhances albuterol-mediated bronchodilation
  6. Ipratropium: especially effective in management of asthma in the elderly (NIH, NAEPP Working Group Report: Considerations for Diagnosing and Managing Asthma in the Elderly
     • (http://www.nhlbi.hib.gov/nhlib/lung/asthma/prof/as_elder.htm)
  7. Ipratropium (Atrovent): treatment of choice for beta-blocker-induced bronchospasm

•  Adverse Effects:
  • Local: dry mouth; pharyngeal irritation
  •  Systemic: (dependent on extent of absorption)
    •  urinary retention
    •  loss of ocular accommodation
    •   tachycardia
    •  agitation
    •   may increase intraocular pressure in patients with glaucoma

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Corticosteroids

• Overview: Corticosteroids
  • Corticosteroid Effects:
    • diminish bronchial reactivity
    • increase airway diameter
    • reduced frequency of asthma attacks

• Mechanisms of Action:corticosteroids
  • primary: inhibition of eosinophil-mediated airway mucosal inflammation pathway in asthmatic airways
  • Principal anti-inflammatory action:
    • inhibition of cytokine productionthis or (probably central for inhaled antigen-initiation of inflammatory cascade
  • secondary: enhancement of beta-receptor agonist effects

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Clinical Use: Corticosteroids in Asthma

•  Due to significant adverse effects associate with chronic corticosteroid administration, oral/parenteral corticosteroids are used:
  1. for management of acutely ill patients
  2. patients not adequately maintained with bronchodilators
  3. patients whose symptoms are worsening, despite reasonable maintenance treatment

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• Corticosteroids for urgent/emergent intervention:
  • oral dose -- 30-60 mg prednisone per day or
  • IV dose -- 1mg/kg methylprednisolone (Solu-Medrol) every six hours
  • daily doses decrease gradually after improvement in airway obstruction
  • systemic corticosteroid treatment: discontinued in 7-10 days (some patient's asthma may worsen at this point)

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• Adrenal Suppression by corticosteroids:
  • Adrenal suppression:
    • dose dependent
    • diurinal variation of corticosteroid secretion
  • administration of corticosteroids: early-morning (after endogenous ACTH secretion)
  • nocturnal asthma: oral/inhaled corticosteroids -- late afternoon

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• Aerosol Treatment:
  • most appropriate way to decrease adverse systemic corticosteroid effects:
  • Effective lipid-soluble corticosteroids -- administered by aerosol:
    •   beclomethasone (Banceril)
    •   triamcinolone (Aristocort)
    •   flunisolide (AeroBid)
    •  fluticasone (Flovent)
    •  budesonide (Rhinocort)

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  •  Toxicities/Cautions/Problems:
    •  in switching from oral to inhaled treatment: taper oral therapy slowly to avoid causing adrenal-insufficiency
    • chronic use of inhaled steroids (may cause adrenal suppression and high dosages); however, the risk is very small with normal doses compared to oral corticosteroid treatment.
    •  Inhaled topical corticosteroids: oropharyngeal candidiasis
      • risk reduced by gargling with water and spitting after each inhalation
    • Hoarseness: local effect -- vocal cords
    • Possible concern: inhaled corticosteroids -- does-dependent linear growth slowing in some children/adolescence (perhaps will effect on final adult height); asthma: delays puberty
    • Suppression of hypothalamic-pituitary-adrenal axis
    • Decreased bone density
    • Cataract formation
    • Dysphoria
    • High doses: 
      • dermal thinning
      • glaucoma

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  • Advantages of inhaled, chronic use of corticosteroids:
    • Regular use: suppress inflammation, decrease bronchial hyper- responsiveness, decrease asthma symptoms in patients with chronic disease
    • reduce symptoms; improve pulmonary function in mild asthma
    • reduces/eliminates need for oral corticosteroids in patients with severe asthma
    • Bronchioles reactivity reduced: maximal reduction may be delayed (9-12 months) after treatment begins
    • May be used as first-line treatment for mild asthma in combination with beta-agonist PRN (10-12 week treatment course; then re-evaluate); dosages may be with time decreased; some patients may be able to stop using the drug completely.
    • commonly prescribed (due to efficacy and safety) for patients who more than occasionally require beta-agonist inhalation

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