07b - Drugs Acting on Respiratory System

respiratory drugs

treat asthma and COPD by opening narrowed airways, reducing inflammation, reducing mucus, or modifying immune/allergic signaling

• open airway → β₂ agonists, anticholinergics

• calm disease progression → corticosteroids, leukotriene modifiers, omalizumab, cromolyn, roflumilast

asthma

airway narrowing caused by bronchoconstriction, airway inflammation, airway hyper-responsiveness, mucus production

• asthma drugs relax squeezing muscle, calm inflammation, or reduce mucus/allergic signaling

COPD

chronic obstructive pulmonary disease involving chronic airflow limitation

• chronic bronchitis → inflamed bronchi, excess mucus, productive cough, airway obstruction

• emphysema → damaged alveoli, loss of elastic recoil, enlarged air spaces, poor gas exchange

corticosteroids

inhaled corticosteroids are preferred for reducing airway inflammation and hyper-responsiveness in asthma

• beclomethasone, budesonide, fluticasone, triamcinolone

• improve lung function

• reduce occurrence of acute asthma exacerbation

• common adverse effects:

  • oropharyngeal candidiasis, dysphonia, diminished compliance

• less common adverse effects:

  • adrenal suppression, bone loss, skin thinning, metabolic changes, behavioral abnormalities, weight gain, decreased linear growth in children

• mechanism:

  • reduce inflammatory gene expression to decrease inflammatory cells and mediators in airway

adrenergic bronchodilators

activate β₂ receptors to relax airway smooth muscle

• mechanism:

  1. stimulation of Gs to increase adenyl cyclase

  2. increased cAMP activates PKA

  3. reduction of smooth muscle contraction, causing airway smooth muscle relaxation

  4. bronchodilation occurs

• epinephrine → subcutaneous injection improves respiratory function

  • chronic treatment with β₂-selective agonist albuterol for longer duration of action and minimum cardiac stimulatory effect

  • not used chronically because it can stimulate heart and cause tachycardia, palpations, increased cardiac workload; used in emergencies

selective β-adrenergic receptor agonists — dobutamine

DOBUTAMINE → β₁ agonist that increases heart rate and cardiac output with no effect on vasculature

• used in heart failure to increase CO and as inotropic support after cardiac surgery

• increases CO without increasing myocardial oxygen demand

• use in caution with atrial fibrillation because it increases AV conduction

selective β-adrenergic receptor agonists — albuterol and terbutaline

ALBUTEROL, TERBUTALINE → short-acting β₂ agonists as bronchodilators in meter-dose inhaler

• albuterol → drug of choice in management of acute asthma

• terbutaline → no longer used in US, but used in other countries to suppress premature labor

• cause tremor, restlessness, apprehension, anxiety

• oral administration may cause tachycardia or arrhythmia (β₁ action) in patients with cardiac disease

  • cardiac effects can occur with higher doses

• contraindicated with MAO inhibitors

selective β-adrenergic receptor agonists — salmeterol and formoterol

SALMETEROL, FORMOTEROL → long-acting β₂-selective agonists as bronchodilators in meter-dose inhalers to cause sustained bronchodilation lasting for 12 hours

• salmoterol → delayed onset

• not recommended for monotherapy, but highly efficacious if combined with corticosteroid

  • does not adequately treat inflammatory component of asthma; inflammation continues and masks disease

• treatment for nocturnal asthma, but shown to increase asthma-related deaths

anticholinergic bronchodilators

block M₃ receptors in airway smooth muscle, preventing bronchoconstriction

• route of administration by inhalation

• synthetic quaternary ammonium congeners of atropine

• competitive antagonists of M₃ receptors in smooth muscle of airway

• classified on half life of agents

  • short-acting → ipratropium (half-life = 0.3 hours)

  • long-acting → tiotropium (half-life = 35 hours)

• adverse effects

  • dry mouth, altered taste, coughing after administration

leukotriene modifiers

reduce leukotriene-driven bronchoconstriction, mucus secretion, and allergic inflammation

• leukotrienes are produced by mast cells, eosinophils, and macrophages from arachidonic acid

  • produce airway smooth muscle cell contraction and muscle secretion, induce allergic inflammatory cells, modulate cytokine production, alter structure in airway

• MONTELUKAST, ZAFIRLUKAST → selective antagonists for cell surface LT₁ receptors

  • reduces airway hyper-responsiveness, eosinophils, and exhaled nitric oxide

  • orally active and well-tolerated

  • treated to dampen leukotriene action in chronic asthma with allergic rhinitis, exercise-induced asthma, and aspirin-sensitive asthma

• ZILEUTON → blocks leukotriene production by chelating iron in active site of 5-lipooxygenase enzyme

  • short half-life and potential liver toxicity

  • contraindicated in liver disease; liver function tests required

monoclonal antibodies — omalizumab

OMALIZUMAB → anti-IgE monoclonal antibody used in allergic asthma

• IgE normally produced by B cells to play critical role in allergic responses in patients with asthma

  • 60-80% of asthma patients have rhinitis; 20-40% of rhinitis patients have asthma

  • binding IgE to receptors on mast cells and basophils initiates inflammatory cascade, causing release of histamine, leukotrienes, and platelet activating factors that elicit smooth muscle contraction, vascular leakage, and secretion of mucus

• omalizumab antibody binds to free IgE and not receptor-bound IgE to downregulate receptor expression on basophils

phosphodiesterase-4 inhibitors — roflumilast

ROFLUMILAST → PDE4 inhibitor that increases cAMP and reduces COPD exacerbations

• PDE4 normally degrades cAMP, resulting in loss of β₂-agonist response

• adverse effects:

  • change in mood or behavior, insomnia, anxiety attacks, depression, acting on dangerous impulse, weight loss

theophylline

THEOPHYLLINE → plant-based alkaloid that increases cAMP by inhibiting PDE3

• elicits smooth muscle relaxation and anti-inflammatory effects → exerted by stimulation of histone deacetylases

• inhibits response to allergen → reduces eosinophil and CD4+ lymphocytes into airway to decrease IL-8 and neutrophil chemotactic response

• narrow therapeutic window → >20 mg/L plasma concentration elicits ventricular arrhythmias, seizures, and death

• adverse effects:

  • headaches, GI reflux, diuresis, repetitive vomiting, restlessness

• serum levels should be monitored

• dosing dependent on smoking history, cardiac disease, and hepatic disease (affects metabolism and clearance)

cromolyn

CROMOLYN → extract of Ammi visnaga plant used for prophylactic treatment of asthma, not for acute asthma attacks

• helps lower corticosteroid and sympathomimetic use

• inhibits early and late asthmatic response

• effective in long-term treatment of chronic asthma

• becomes effective after 4 weeks of treatment

• inhibits release of mediators from mast cells and other inflammatory cells

• inhibits afferent pulmonary nerve fiber receptors that contribute to reflex bronchoconstriction

• least toxic medication for asthma

• mild adverse effects:

  • wheezing, coughing, dryness of throat

  • rare reports of eosinophilia with pulmonary infiltration or pulmonary granulomatosis

antitussives and expectorants

antitussives and expectorants treat mild respiratory illnesses, suppressing cough reflex

• codeine, benzonatate, dextromethorphan, noscapine

pharmacotherapy for asthma

asthma pharmacotherapy is stepwise, increasing treatment if asthma is no controlled, and stepdown if well-controlled for at least 3 months

1. short-acting beta-agonist PRN

2. low-dose inhaled corticosteroid

3. low-dose inhaled corticosteroid + long-acting beta-agonist OR medium-dose inhaled corticosteroid

4. medium-dose inhaled corticosteroid + long-acting beta-agonist

5. high-dose inhaled corticosteroid + long-acting beta-agonist

   • consider omalizumab for allergies

6. high-dose inhaled corticosteroid + oral corticosteroid

   • consider omalizumab for allergies

• use of short-acting beta-agonist >2 days a week for symptom relief indicates inadequate control and need to step up treatment

pharmacotherapy for COPD

COPD pharmacotherapy is guided by severity using FEV₁/FVC and FEV₁ predicted values

1. mild → FEV₁/FVC < 0.7; FEV₁ > 80% predicted

2. moderate → FEV₁/FVC < 0.7; 50% < FEV₁ < 80% predicted

3. severe → FEV₁/FVC < 0.7; 30% < FEV₁ < 50%

4. very severe → FEV₁/FVC <0.7; FEV₁ < 30% predicted or FEV₁ <50% + chronic respiratory failure

• treatment for all stages to reduce risk factors, influenza vaccination, short-acting bronchodilator when needed

  • moderate and above → add regular treatment with one or more long-acting bronchodilators, add rehabilitation

  • severe/repeated exacerbations → add inhaled glucocorticoids if repeated exacerbations

  • very severe / chronic respiratory failure → add long-term oxygen, consider surgical treatments

dental implications for respiratory disease

• anxiety can precipitate respiratory symptoms

• dental materials that contain powders can increase patient’s airway obstruction if inhaled

• aspirin and aspirin-containing medications should be avoided if there is questionable intolerance or nasal polyps because aspirin can induce asthma

• opioids (hydrocodone) and large doses or morphine can produce bronchoconstriction by causing histamine release from mast cells, decreasing respiratory drive

• hypoxia in COPD patients can cause oral complications like difficulty healing after surgery or difficulty in fighting infections

• corticosteroids can lead to oral candidiasis due to reduced oral defenses against infection

• long-term cigarette smoking places patients with COPD at higher risk for oral cancer

• emergency preparedness:

  • dentists and staff should be prepared to manage emergency exacerbations in patients with respiratory disease

  • use 2-4 puffs of short-acting β-agonists for acute exacerbations in 20 minute intervals

  • additional therapy with oral corticosteroid or anticholinergic in incomplete or poor response

  • epinephrine 0.2-0.5 mg given subcutaneously for severe episodes