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)

• Widely used sympathomimetic drugs

  • Epinephrine -- significant ß₁ receptor activation (cardiac effects)

  • Ephedrine

  • Isoproterenol -- significant ß₁ receptor activation (cardiac effects)

  • ß₂ receptor selective agents

• Some ß₂ receptor receptor selective drugs

  • Albuterol (Ventolin,Proventil) 

  • Bitolterol (Tomalate) 

  • Terbutaline (Brethine) 

  • Metaproterenol (Alupent)

  • Salmeterol (Serevent) 

• Epinephrine

  • Rapidly acting bronchodilator (subcutaneously route of administration;inhalation {microaerosol}

  • Useful in asthma emergency, but now typically superceded by ß₂ selective agents

  • Side Effects: Significant ß₁ and ß₂ receptor activation:

    •  Tachycardia

    •  Other arrhythmias

    •  Exacerbate angina

• Ephedrine

  • Relative to epinephrine, ephedrine is orally active and exhibits

    • Longer duration of action

    • More CNS effects

    • Low-potency

  • Used infrequently in asthma management

• Isoproterenol (Isuprel)

  • Potent bronchodilation;

  • Administered: micro-aerosol; aerosol solutions

• ß₂ receptor-selective agents

  • Most effective drugs (by inhalation) for treatment to acute bronchospasm and for prevention of exercise-induced asthma

  • 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: terbutaline (used for asthma emergency, in the absence of aerosol availability)

• 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

•  Concerns about long-term/acute sympathomimetic use

  • Hypothesis: β-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

• 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

Muscarinic Antagonists

• 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)

• 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

  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

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

  • Clinical Use: Corticosteroids in Asthma

    •  Due to significant adverse effects associated 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

    • 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)

    • 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

    • 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)

    •  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

    • Advantages of inhaled, chronic use of corticosteroids:

      • Regular use: suppresses inflammation, decreases 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

   

   

  Leukotriene Pathway Inhibitors

  • Background

    • Leukotriene production:

      • Action to 5-lipoxygenase on arachidonic acid

      • Synthesized by inflammatory cells found in the airway, including:

        •  Eosinophils

        •  Macrophages

        •  Mast cells

        •  Basophils

      • Leukotriene B₄ (neutrophil chemoattractant), leukotriene C₄, and leukotriene D₄ provoke symptoms consistent with those seen in asthma:

        •  Bronchoconstriction

        •  Mucosal edema

        •  Mucus hypersecretion

        •  Increase bronchial reactivity

  • Interruption of leukotriene pathways

    • Inhibition of 5-lipoxygenase-- zileuton  

      • Rationale: prevents leukotriene synthesis

      • Effective for maintenance treatment of asthma

      • Requires monitoring for hepatic toxicity

      • Metabolized by cytochrome P450 1A2, 2C9, 3A4:

        • Can decrease clearance; increasing concentration of:

          •  Theophylline

          •  Warfarin (Coumadin)

          •  Propranolol (Inderal)

    • Inhibition of leukotriene D₄ receptor binding -- zafirlukast (Accolate), montelukast (Singulair)

      • Zafirlukast (Accolate)

        • Modestly effective for maintenance treatment in mild to moderate asthmatics

        • Less effective than inhaled beclomethasone

        • Bioavailability decreases significantly with food

        • Theophylline may also decrease its effect

        • Zafirlukast: increases serum concentration of oral anticoagulants (made provoke bleeding)

      • Montelukast (Singulair)

        • Leukotriene D₄ receptor antagonist

        • Modestly effective for maintenance treatment of adults and children with intermittent/persistent asthma

        • Less effective than inhaled corticosteroids (addition to montelukast may reduce corticosteroid dosage requirement)

        • Montelukast, added to oral/inhaled corticosteroids, improves asthma patients with aspirin-intolerant asthma

        • Only leukotriene drug FDA approved for use in children 6 to 12 years old.

          • Orally effective; may be especially effective in reducing response to aspirin in those asthmatics very sensitive to aspirin

  • Other drug groups possibly beneficial in asthma management

    • Calcium channel blockers

    • Nitric oxide donors

    • Potassium channel activators

    • Anti-IgE Monoclonal Antibodies

   

   

  • ¹ McFadden, E.R., Jr. "Asthma: Diseases of the Respiratory System" in Harrison's Principles of Internal Medicine, 15th Edition (Braunwald, E., Fauci, A.S., Kasper, D.L., Hauser, S.L, Longo, D.L. and Jameson, J.  Larry, eds) pp. 1456-1463,  McGraw-Hill Medical Pubishing, Division, New York, 2001

  • ² Kelley, H. William, "Asthma" in  Pharmacotherapy:  A Pathophysiologic Approach, (Dipiro, J.T., Talkbert, R.L.  Yee, G.C., Matze, G.R., Wells, B.G. and Posey, L. Michael, eds.)  pp 430-459. McGraw-Hill Medical Pubishing, Division, New York, 1999.

  • ³Spencer SM., Sgro JY., Dryden KA., Baker TS., Nibert ML. (1997) Rhinovirus 14 (3D image reconstruction from electron microscopy data) Journal of Structural Biology. 120(1):11-21

  • ⁴Attribution:  Michigan State University Website

  • ⁵State University of New York, Upstate Medical University, Cytotechnology, On-Line Courseware

  • ⁶Steve Dewhurst, Ph.D., Structure of the CC-chemokine, RANTES, (c) University of Rochester and Stephen Dewhurst, 1999

  • ⁷Ealick SE, Recombinant Human Granulocyte-Macrophage Colony-Stimulating Factor, Cornell University

    • Walter MR, Cook WJ, Ealick SE, Nagabhushan, TL, Trotta, PP and Bugg, CE. Three-Dimensional Structure of Recombinant Human Granulocyte-Macrophage Colony-Stimulating Factor, J. Mol. Biol. 224:1075-1085 (1992).

    • Reichert P, Ealick SE, Cook WJ, Trotta P, Nagabhushan TL, Bugg CE. Crystallization and Preliminary X-ray Investigation of Human Granulocyte-Macrophage Colony Stimulating Factor, J. Biol. Chem. 265(1):452-453 (1990)

  • ⁸Williams, TJ and Conroy, TM  Eotaxin and the attraction of eosinophils to the asthmatic lung, Respir Res 2001, 2: 150-156

  • ⁹McFadden, Jr., E. R., Diseases of the Respiratory System: Asthma, In Harrison's Principles of Internal Medicine 14th edition, (Isselbacher, K.J., Braunwald, E., Wilson, J.D., Martin, J.B., Fauci, A.S. and Kasper, D.L., eds) McGraw-Hill, Inc (Health Professions Division), 1998, p 1422.

  • ¹⁰Daroca, P, Lung and Respiratory System Review, Tulane University Pathology, (Figure & caption attribution)