Anesthesia Pharmacology Chapter 19:  Co-Existing Conditions (Asthma)

 

• 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 and 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 -- 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: 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 and 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-- consequence: death/severe toxicity

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: 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

• 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) (pictured above)

  • ipratropium bromide available in combination with albuterol (Combivent)

• Compare impratropium structure to that of atropine: 

• 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

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

• ⁵State University of New York, Upstate Medical University, Cytotechnology

• 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 and caption attribution)