Medical Pharmacology Chapter 25:  Pulmonary Pharmacology

 

• 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):

      • Yoluene 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 &  hay fever

•   Adverse/Side effects: cromolyn (localized effects (sites of 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: 3,7 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 inhibits 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 diuretic, 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 ß₂-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 with the consequence of death or 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.

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• ⁴Attribution:  Michigan State University Website

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

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

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  • 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)