ASTHMA AND RESPIRATORY AGENTS

pathological features of asthma

• lymphocytic, eosinophilic inflammation of the bronchial mucosa

• “remodeling” of the bronchial wall

• thickening of the lamina reticularis beneath the epithelium

• hyperplasia of the bronchial vasculature, smooth muscle, secretory glands, and goblet cells

pathophysiologic features of asthma

• marked increase in bronchial responsiveness to inhaled stimuli

• reversible narrowing of the bronchial airway

clinical features of asthma

• shortness of breath

• chest tightness

• wheezing

• coughing

early reaction phase

• allergen exposure causes synthesis of IgE, which binds to mast cells

• on re-exposure to allergen, antigen-antibody interaction on mast cell surfaces triggers release of mediators of anaphylaxis

mediators of anaphylaxis

• histamine, try-take, prostaglandin D2, leukotriene C4, and platelet activating factor

  • provoke contraction of airway smooth muscle

  • immediate fall in forced expiratory volume in 1 sec

• interleukins 4 and 5, granulocyte-macrophage colony-stimulating factor, tumor necrosis factor, and tissue growth factor from T cells and mast cells

  • produces late reaction phase by activating eosinophils and neutrophils

late reaction phase

• eosinophils and neutrophils

  • edema, mucus hypersecretion, smooth muscle contraction

  • increase in bronchial reactivity associated with the late asthmatic response

  • indicated by a second fall in FEV₁ 3-6 hours after the exposure

drugs effecting smooth muscle for asthma

• beta agonists, methylxanthines, tiotropium

• dilators

drugs effecting cell infiltration, eosinophils, and T lymphocytes for asthma

inhaled corticosteroid

drugs effecting mast cells for asthma

cromones and inhaled corticosteroids

drugs effecting leukotrienes for asthma

anti-leukotrienes

drugs effecting IgE for asthma

anti-IgEs

drugs effecting IL-4 and IL-5 for asthma

-mab

asthma big three

• airway obstruction that is partially reversible

• airway inflammation

• airway hyper-responsiveness

chronic obstructive pulmonary disease (COPD)

• predominate of neutrophils, macrophages, cytotoxic T lymphocytes, and T helper-17 cells

• predominantly affects small airways

  • progressive small-airway narrowing and fibrosis (chronic obstructive bronchiolitis

  • destruction of the lung parenchyma with destruction of the alveolar walls (emphysema)

• results in airway closure on expiration, leading to air trapping and hyperinflation, particularly on exercise

asthma characteristics

• intermittent airflow obstruction

• improvement with bronchodilators and steroids

• reversibility with treatments

• cellular inflammation with mast cells, eosinophils, IgE mediated; leukotrienes, IL, PGD

• airway remodeling

• hyperresponsiveness

COPD characteristics

• progressively worsening airflow obstruction

• maintenance with bronchodilators

• more permanent airflow obstruction

• neutrophils, macrophages, cytotoxic T lymphocytes

• alveolar destruction, mucous hyper secretion, fibrosis

• chronic bronchitis

• emphysema

route of delivery for asthma drugs

inhalation

bronchodilators

• B₂ adrenergic agonists (sympathomimetics)

• theophylline (a methylxanthine)

• anticholinergic agents (muscarinic receptor antagonists)

B₂ adrenergic agonist indirect effects

inhibit release of bronchoconstrictor mediators from inflammatory cells and of bronchoconstrictor neurotransmitters from airway nerves

• prevent mediator release from mast cells

• prevent microvascular leakage and thus the development of bronchial mucosa edema

• may enhance mucociliary clearance

• reduction in neurotransmission in human airway cholinergic nerves (inhibit acetylcholine release)

short-acting B₂ adrenergic agonists (SABA)

• quick relievers

• treat asthma

• effective in protecting against various asthma triggers (exercise, cold air, allergens)

• bronchodilators of choice in treating acute severe asthma

• not a controller medication

what drugs are SABAs

albuterol and levalbuterol

SABA other dosage forms

• albuterol and terbutaline oral form

• terbutaline subcutaneous inj

albuterol and terbutaline oral form characteristics

• 1 t bid or tid

• adverse effects: skeletal muscle tremor, nervousness, and occasional weakness

• rarely prescribed

terbulatine SQ inj characteristics

• indication are similar to those for SQ epinephrine: severe asthma requiring emergency treatment when aerosolized therapy is not available or has been ineffective

• has longer duration of action meaning that cumulative effects may be seen after repeated injections

long-acting B₂ adrenergic agonists (LABA)

• controller

• bronchodilator action of more than 12 h and protect against bronchoconstriction for a similar period

  • high lipid solubility permits them to dissolve in the smooth muscle cell membrane in high concentrations

• improve asthma control (when given bid) compared with regular treatment with SABAs (4-6 x daily)

LABA drugs

salmeterol, formoterol, arformoterol

ultra long-acting B₂ adrenergic agonists (ULABA)

• used once daily and are more effective in patients with COPD

• usually combined with an ICS or antimuscarinic agent

ULABA drugs

indacaterol, vilanterol, olodaterol

in patients with asthma, _____

LABAs should always be used in combination with an ICS in a fixed-dose combination inhaler

in patients with COPD, _____

LABA are effective bronchodilators that may be used alone or in combination with anticholinergics or ICSs

B₂ adrenergic agonists adverse effects

• muscle tremor

• tachycardia

• hypokalemia (low potassium)

• restlessness

• metabolic effects

methylxanthines

• theophylline, theobromine, caffeine

• not used as frequently due to toxicity and more effective therapies

• requires monitoring of serum levels with narrow therapeutic window

• aminophylline, a theophylline-ethylenediamine complex used in inpatient setting

• nebulizer B₂ agonists are now preferred over IV aminophylline for acute exacerbations of asthma and COPD

methylxanthines MOA

• thought to inhibit phosphdiesterasees and therefore increase cAMP

• antagonizes adenosine receptors at therapeutic concentrations

• releases interleukin-10 which has a broad spectrum of anti-inflammatory effects

theophylline pharmacokinetics and metabolism

• has anti asthma effects other than bronchodilation below 10mg/L

  • therapeutic range is now taken as 5-15 mg/L

  • clinical benefit in asthma and COPD at plasma concentrations less than 10 mg/L

  • measured 4 hrs after the last dose with slow-release preparations when steady state has been achieved

• metabolized in the liver, mainly by CYP1A2

• rapidly and completely absorbed, but larger inter-individual variations in clearance due to differences in hepatic metabolism

factors increasing clearance of theophylline

• CYP1A2 induction (rifampicin, barbiturates, ethanol)

• smoking (tobacco, marijuans) via CYP1A2 induction

• high-protein, low-carbohydrate diet

• barbecued meat

• childhood

factors decreasing clearance of theophylline

• CYP inhibition (cimetidine, erythromycin, ciprofloxacin, allopurinol, fluvoxamine, zileuton, zafirlukast)

• cognitive heart failure

• liver disease

• pneuomonia

• viral infection and vaccination

• high-carbohydrate diet

• old age

theophylline adverse effects

• more often at concentration greater than 15 mg/L

• headache, nausea, vomiting, abdominal discomfort, and restlessness

• behavioral disturbances and learning difficulties in schoolchildren

• cardiac arrhythmias

• seizures