Nursing Pharmacology Chapter 25:  Pulmonary Pharmacology: Asthma

"Asthma Treatment and Nursing Care"

McClintock M "Asthma Treatment and Nursing Care" "This video is designed for nursing students and includes asthma treatment, drug therapy, nursing care, and nursing diagnoses. Additional materials including instructor notes, assessment videos. and games are available on our website at www.pocketprofnursing.com." https://www.youtube.com/watch?v=YwBgZsUHEks

• Rationale for Pharmacological Intervention

  • Pharmacological approaches suggested by multiple pathogenic mechanisms:

    • Reduction of mast cell degranulation

      • Sympathomimetic agents

      • Calcium channel blockers

      • Cromolyn/nedocromil

    • Reduction of cholinergic influence from vagal motor nerves

      • Antimuscarinic agents

    • Direct relaxation of airway smooth muscle

      • Sympathomimetic drugs

      • Theophylline

Pharmacological Agents Used in Asthma Management

Cromolyn (Intal) and  Nedocromil (Tilade)

• Overview

  • These agents must be used prophylactically by aerosol (metered-dose inhalers).  Cromolyn and Nedocromil inhibit:

    1. Antigen & exercise-induced asthma

    2. Bronchial reactivity

  • Cromolyn and Nedocromil have no direct effect on airway smooth muscle tone and will not reverse asthmatic bronchospasm

• Cromolyn: (Intal)

  • Poorly absorbed

  • Administered by microfine powder inhalation or aerosol

  • Absorption: approximately 10%

  • No bronchodilating activity

• Nedocromil: (Tilade)

  • Also poorly absorbed; low bioavailability;

  • Aerosol form only

• Mechanism of Action: cromolyn and nedocromil

  • Alters function of delayed chloride channels (best demonstrated for nedocromil) and inhibits cell activation

  • Chloride-mediated channel effects:

    1.  Inhibition of cough

    2.  Inhibition of early response to antigens (mast cells)

       • Mast cells specific (cromolyn --minimal mediator released inhibition on human basophils)

    3.  Inhibition of late response to antigens (eosinophils)

• Clinical Use:

  • Cromolyn (Intal) pre-treatment

    •  Blocks bronchoconstriction due to antigen inhalation

    •  Blocks aspirin-induced bronchoconstriction

    •  Blocks bronchoconstriction induced by environmental agents (causes of occupational asthma)

      • Toluene diisocyanate

      • Wood dusts

      • Soldering fluxes

      • Piperazine hydrochloride

      • Certain enzymes

    • Reduces bronchodilators medication requirements and symptomatic severity in patients with perennial asthma

    • Cromolyn (chronic treatment) appears to decrease the bronchial hyperreactivity:

      •  Airway protection against inflammatory, chemical anaphylaxis mediators

      •  More effective in reducing seasonal increases in bronchial reactivity (allergic asthma) but less effective when compared with inhaled corticosteroids.

    • Cromolyn (Intal): -- effective in reducing symptoms of allergic rhinitis and hay fever

•   Adverse/Side effects: cromolyn side effects are usually localized effects close to the site of drug deposition.

  • Throat irritation

  • Cough

  • Mouth dryness

  • Wheezing

  • Chest tightness

• Additional comments:

  • Nedocromil: (Tilade) is equal potent to standard doses of inhaled corticosteroids (in moderate asthmatics) and improved asthma control may be obtained by addition of nedocromil to standard dosage of inhaled corticosteroids

Methylxanthines -- (theophylline: some utility in asthma treatment; theobromine;caffeine: major sources (tea, cocoa, coffee)

• Chemistry

  • Theophylline: 1,3-dimethylxanthine

  • Theobromine: 37 dimethylxanthine

  • Caffeine: 1,3,7-trimethylxanthine

  • Most commonly used theophylline preparation is aminophylline (theophylline-ethylenediamine complex)

  • Dyphylline (synthetic theophylline analog): less potent; shorter acting

  • Metabolic products include demethylated xanthines (not uric acid) which are excreted in the urine.

• Proposed mechanisms of action: no mechanism has been established to account for bronchodilation methylxanthine effects.

  1. High concentrations (may not be reached in vivo): phosphodiesterase inhibition

     • Results in increased intracellular cAMP which may account for:

       • Cardiac stimulation

       • Smooth muscle relaxation

  2. Inhibition of adenosine cell surface receptors (modulators of adenylyl cyclase activity)

     • Adenosine: isolated airway smooth muscle contraction

     • Histamine release from lung cells

     • Both effects antagonist by theophylline

     • Other xanthine agents without adenosine-antagonistic characteristics are more potent than theophylline in bronchoconstriction inhibition

  3. Anti-inflammatory action:

     • Low-dose theophylline: inhibit late response to antigenic challenge

• Overview  Pharmacodynamics

  • Multiple methylxanthine effects

    • CNS

    • Kidney

    • Cardiac/skeletal muscle

    • Smooth muscle

      •  Theophylline: smooth muscle effects dominate

      •  Caffeine: CNS effects most prominent

  • Central Nervous System Effects

    • Increased alertness; reduced fatigue

    • In more sensitive individuals: caffeine -- nervousness/insomnia

    • Very high methylxanthine doses: medullary stimulation, convulsions

    • Primary side effect in patients requiring aminophylline (large doses) for control of asthma: nervousness & tremor

  • Cardiovascular Effects

    • Direct positive chronotropic

    • Direct enhanced myocardial contractility

    • Mechanism of Effects:

      •  Low doses: increased catecholamine release secondary to inhibition of presynaptic adenosine receptors

      •  High doses: cAMP-mediatedspace for (secondary to phosphodiesterase inhibition) enhanced calcium influx

    • Reduced blood viscosity: unknown mechanism

      •  Pentoxifylline (Trental): management of intermittent claudication.

  • Gastrointestinal Tract Effects

    • Methylxanthines: enhanced secretion of gastric acid and digestive enzymes

    • Coffee (decaffeinated) -- stimulates secretion; secretagogue not caffeine

  • Renal Effects

    • Weak diuretics  (not therapeuticly important)

      • Increased glomerular filtration

      • Reduced tubular sodium reabsorption

  •  Smooth Muscle Effects

    • Major Therapeutic Effect: Bronchodilation

      •  Adverse Effects: dose limiting

  • Skeletal Muscle Effects

    • Enhanced skeletal muscle contraction

    • May improve contractility; responsible for reversing diaphragmatic fatigue in COPD patients.

    • In patients with airflow obstruction improved diaphragm skeletal muscle contraction may enhance ventilatory response to hypoxia and reduce dyspnea

• Methylxanthines: Clinical Use

  • Theophylline: most effective xanthine bronchodilator

  • Relieves airway obstruction:

    •  In acute asthma

    •  Reduces symptoms severity;

    •  In chronic asthma:reduces off-time from work or school in chronic asthma

  • Theophylline:Less effective bronchodilator compared to inhaled beta2-agonists

    •  Slower onset of action

    •  Some modest anti-inflammatory effect

    •  Relatively limited usefulness in acute asthma, compared other drugs, theophylline:

      • Decreased frequency and severity of symptoms in chronic asthma

  • Theophylline base: slightly water soluble; often administered as salts containing various amounts of theophylline base:

    •  Aminophylline: 86% theophylline (by weight)

    •  Oxtriphylline: 64% theophylline (by weight)

  •  Concerns: Theophylline Blood Levels

    • Therapeutic/toxic effects: related to plasma concentration

    • Pulmonary function improvement: effective plasma concentration range: 5-20 mg/L.

    • At concentrations > 20 mg/L:

      • Nausea, headache, insomnia, nervousness

    •  Higher concentrations (> 40 mg/L) leads to:

      •  Seizures, neuromuscular irritability, tremor,

      •  Arrhythmias,hypokalemia, hyperglycemia, vomiting

    • Reasonable theophylline administration: pharmacokinetics crucial

  •  Factors affecting theophylline administration/ blood levels

    • Loading dose: given slowly; "IV push" may induce transient toxicity (seizures/cardiac arrhythmias)

    • Plasma clearance: wide variation

      •  Decreased liver function may cause toxic theophylline levels (theophylline is hepatically metabolized)

        • Changes in hepatic function:

          • Reduced blood flow secondary to heart failure

          • Attenuated function due to hepatic cirrhosis

          • Increased metabolism due to hepatic enzyme induction (dietary/cigarette smoking)

  • Oral theophylline, although effective, is not a primary agent in maintenance treatment:

    • Improves long-term asthma control as monotherapy or when added to inhaled corticosteroids

    • Minor side effects -- insomnia

    • Risk of accidental/intentional overdosage:  cpossible onsequence: death/severe toxicity

• 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)