Sympathomimetic Drugs

• Overview-- pharmacological actions
  • relax airway smooth muscle
  • inhibit release of some mast cell bronchoconstrictive mediators
  •  may inhibit microvascular leakage
  •  may increase mucociliary transport
  • these agents stimulate adenylyl cyclase, increasing cAMP formation in airway tissue
• ß₂ receptor activation:
  • relaxation of airway smooth muscle
  • mediator release inhibitor
  •  skeletal muscle tremor (toxicity)

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• Widely used sympathomimetic drugs:
  • epinephrine -- significant ß₁ receptor activation (cardiac effects)
  • ephedrine
  • isoproterenol -- significant ß₁ receptor activation (cardiac effects)
  • ß₂ receptor selective agents

• Epinephrine:
  • Rapidly acting bronchodilator (subcutaneously route of administration;inhalation {microaerosol}
  •  useful in asthma emergency
  •  Side Effects: Significant ß₁ and ß₂ receptor activation:--
    •  tachycardia
    •  other arrhythmias
    •  exacerbate angina
• Ephedrine:
  • relative to epinephrine:
    • longer duration of action
    • orally active
    • more CNS effects
    • low-potency
  • used infrequently in asthma management

• Isoproterenol: (Isuprel)
  • potent bronchodilation;
  • administered: micro-aerosol; aerosol solutions

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• ß₂ receptor-selective agents
  • Most effective drugs (by inhalation) for treatment to acute bronchospasm and for prevention of exercise-induced asthma
    • Regular use of short-acting ß₂ receptor agonists offer go to manage over PRN use
  • Most prominent sympathomimetic drugs used for asthma management
  • Effective after oral administration or inhalation
  • Long duration of action
  • Significant ß₂ receptor selectivity
  •  Bronchodilation (similar to that produced by isoproterenol); maximal bronchodilation in 30 minutes -- duration 3-4 hours
  •  Route of administration:
    • inhalation
    • oral for albuterol (Ventolin,Proventil), metaproterenol (Alupent) and, terbutaline (Brethine)
      • side effects: skeletal muscle tremor, nervousness
    • subcutaneous: terbutalinespace for (used for asthma emergency, in the absence of aerosol availability)

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• Longer acting ß₂ receptor-selective agents
  • Salmeterol (Serevent): increased duration of action
    • 12 hours or more
    • potent, selective ß₂ receptor-selective drug
    • Mechanism for long duration:
      • high lipid solubility-- (creates a depot effect)
    • Routes of administration:
      • oral
      • inhalation-- greatest airway effect
      • parenteral

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• Concerns about long-term/acute sympathomimetic use:
  • hypothesis: beta adrenergic agonists worsen clinical asthma by inducing tachyphylaxis
    • status: unestablished
  • hypothesis: association between mortality risk from asthma and increased beta-agonist use
    • status: no apparent relationship between risk of death from asthma with use of beta-agonist drugs (oral or metered-dose inhaler route of administration)-- increased incidence of death probably reflects worsening of disease
  • hypothesis: arterial oxygen tension may decrease after beta-agonist use
    • status: true, with transient worsening of ventilation/perfusion mismatching; effect usually small; additional oxygen may be required
  • hypothesis: enhanced myocardial cardiotoxicity from inhaler propellants (fluorocarbons) -- due to myocardial catecholamine sensitization.
    • status: sensitization at high fluorocarbons concentrations; above those obtained through normal inhaler use

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• Inhaler Delivery Devices: Propellants
  • Fluorocarbons-based propellants: changed for environmental reasons
  • New propellants: hydrofluoroalkanes -- smaller particle size; may deliver increased drug amounts
  • Other delivery systems:
    • Dry Powder Inhalers-- activated by inspiration (no propellant used)
      •  children may not be capable of activating these inhalers
      • may deliver less consistent doses

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