Pulm drugs Flashcards
Methacholine
Methacholine is primarily used to diagnose bronchial hyperreactivity,which is the hallmark of asthma and also occurs in chronic obstructive pulmonary disease.
This is accomplished through the bronchial challenge test, or methacholine challenge, in which a subject inhales aerosolized methacholine, leading to bronchoconstriction (PNS). Other therapeutic uses are limited by its adverse cardiovascular effects, such as bradycardia and hypotension, which arise from its function as a cholinomimetic.
Terbutaline (oral, subcutaneous)
Metaproterenol (nebulizer, oral)
Pirbuterol
Albuterol (nebulizer, oral)
(all have inhaler delivery)
They all have “ter”
Short acting Beta2 selective agonist
Little rationale for choice among SABAs. • Maximal bronchodilation is achieved in 15-30 minutes and persists 3-4 hours. • Used for relief of acute asthma symptoms and bronchospasm.
Inhalation (via inhaler or nebulizer) is the preferred route of delivery for
maximal local effect on airway smooth muscle with minimal systemic toxicity.
Beta agonist effects stimulate adenylyl cyclase and increase levels of cAMP decreasing bronchial tone and increasing bronchodilation.
Most widely used bronchodilators in the treatment of asthma.
• Several pharmacologic roles in the treatment of asthma:
Relax bronchial smooth muscle.
Inhibit the release of bronchoconstricting substances from mast cells
Salmeterol
Formoterol
Salmeterol (Serevent®) - partial
Formoterol - full
These are long acting beta2 selective agonist
- Potent selective b2 agonists that are delivered by metered-dose or dry powder inhalers.
- Duration of action is ≥12 hours, due to high lipid solubility.
- They are not recommended as monotherapy for asthma, since they lack any anti-inflammatory actions.
- They work well with inhaled corticosteroids to improve asthma control.
• Aerosolized salmeterol-fluticasone (Advair®) and
formoterol-budesonide (Symbicort®) combinations
are available.
Advair
Symbicort
Aerosolized salmeterol-fluticasone (Advair®)
formoterol-budesonide (Symbicort®) combinations are available.
Theophylline
Aminophylline
They are PDE 3 and 4 inhibitors which prevents the breakdown of cAMP.
Potent bronchodilators, with relaxation of airway smooth muscle being the
major therapeutic action in asthma.
• Effective in relieving airflow obstruction and reducing severity of symptoms.
• Improve contractility of isolated skeletal muscle, and can reverse fatigue of
the diaphragm in patients with COPD.
• Administered orally and parenterally.
• Theophylline is only slightly soluble in water. Improved solubility obtained
with salt formulations that dissociate in water to yield theophylline.
Potential toxicities associated with theophylline use mandate
occasional measurement of plasma levels of the drug.
5-20 mg/L > improved pulmonary function
>20 mg/L > nausea, vomiting, insomnia, irritability, and transient diuresis
>40 mg/L > seizures, arrhythmias, hypotension and shock
• The narrow therapeutic window has limited theophylline use to cases where persistent symptoms are inadequately controlled by anti-inflammatory
agents together with an “as needed” SABA.
Metabolized by CYP3A4 system. Clarithromycin- a macrolide antibiotic is commonly used in the treatment of URI and skin infections. It can potentiate the effects of theophylline.
Ipratropium bromide
Atropine (pulm)
Short acting muscarinic receptor antagonists
Induces bronchodilation by blocking cholinergic stimulation • Is not anti-inflammatory • Does not decrease bronchial hyperresponsiveness over time
Advent of inhaled b-agonists had caused use of anticholinergic agents
to decline. • Interest has been renewed due to realization that parasympathetic
pathways are important in bronchospasm in some asthmatics.
[Atropine]
Low doses cause bronchodilation without increasing heart rate.
• Bronchodilation persists for 5 hours.
• Adverse effects from systemic absorption include urinary retention,
tachycardia, loss of visual accommodation (pupil constriction and contraction of ciliary muscle) , and agitation.
[Ipratropium Bromide]
• A selective quaternary ammonium (cationic) derivative of atropine.
• Can be delivered to airways in high doses because it is poorly absorbed
and does not readily enter the CNS. • In combination with a SABA, bronchodilation exceeds that of either agent alone (useful when symptoms are inadequately controlled by SABA alone).
• Aerosolized combinations with albuterol include Combivent® (metered-dose inhaler) and DuoNeb® (nebulizer).
Combivent
Duoneb
Combivent - albuterol + ipratropium bromide (inhaler form)
Duoneb - albuterol + ipratropium bromide (nebuilzer)
Beclomethasone (QVAR®, Vanceril®) Budesonide (Pulmicort®) Flunisolide (AeroBid®) Fluticasone (Flovent®), Mometasone (Asmanex®) Ciclesonide
Inhaled corticosteroids (ICSs) are now first-line agents for the treatment of chronic asthma in patients of all ages and severity of disease.
• Do not relax airway smooth muscle directly, but do reduce bronchial
reactivity.
• Most important action with regard to alleviating airway obstruction is inhibition
of mucosal inflammation in asthmatic airways.
• Reduce the frequency of asthma exacerbations if administered chronically,
and potentiate the effects of b-agonists.
• Due to severe adverse effects when given chronically, systemic
corticosteroids (e.g., oral prednisone) are reserved for patients with acute
severe asthma who do not respond adequately to bronchodilator therapy.
• Aerosol treatment is most effective way to decrease systemic adverse
effects.
• The development of lipid-soluble corticosteroids has made it possible for delivery to airways with minimal systemic absorption.
Adverse Effects of Inhaled Corticosteroids:
• Local adverse effects include oropharyngeal candidiasis and dysphonia
(caused by corticosteroid-induced myopathy of the vocal cords).
• Inhalation therapy is remarkably free of other complications in adults
(except at very high doses).
• Reduction in growth rate of 1 cm in children during first year, but none
thereafter.
What are the side effects of glucocorticoid therapy after days, months
What are side effects after months to years
Days to months
•Measures of bone metabolism (osteocalcin)
•Markers of HPA-axis function (cortisol) - suppresses
•Inhibits Collagen synthesis in skin
Months - years •Adrenal insufficiency •Osteoporosis •Retardation of pediatric bone growth •Cataracts •Skin effects •Hypertension •Obesity •Psychiatric (psychosis)
Zarfirlukast
Montelukast
Zileuton
Zarfirlukast (LTD4 receptor antagonist)
Montelukast (LTD4 receptor antagonist)
Zileuton (5-lipoxygenase inhibitor)
• Leukotrienes are extremely potent bronchoconstrictors.
• They are associated with mucus hypersecretion, increased bronchial
reactivity, and mucosal edema.
• Thus, inhibiting the synthesis or actions of leukotrienes can provide
effective asthma therapy.
• Two approaches to interrupting leukotriene pathway have been pursued:
- Inhibition of 5-lipoxygenase, thereby preventing leukotriene synthesis.
- Inhibition of the binding of leukotriene D4 to its receptor, thereby preventing its action.
• All are effective in blocking airway responses to exercise and to antigen
challenge.
• Their effects on symptoms, airway caliber, bronchial reactivity, and airway
inflammation are less pronounced than the effects of inhaled corticosteroids,
but are equally effective in reducing frequency of exacerbations.
• Principal advantage is that they can be taken orally, as some patients (e.g.,
children) comply poorly with inhaled therapies.
• Some patients exhibit particularly favorable responses, while others respond
only weakly.
• Among the three drugs, zileuton is the least prescribed, since it requires 4x daily dosing, compared to 1x and 2x daily dosing for montelukast and
zafirlukast, respectively.
Omalizumab
IgE interactions with receptors on mast or other inflammatory cells are thus inhibited, which, in turn, prevents activation of these cells.
• Omalizumab (Xolair®) is a “humanized” murine monoclonal antibody that forms complexes with circulating free IgE and inhibits IgE binding to mast
cells and basophils.
• Subcutaneous administration lowers plasma IgE to undetectable levels.
• Clinical studies revealed that omalizumab lessens the frequency and
severity of asthma attacks, while also reducing corticosteroid requirements.
• Reduced exacerbations requiring hospitalization by 88%, thereby justifying the high treatment cost ($10,000-$12,000 per year) in selected individuals with severe disease characterized by frequent exacerbations.
• Adverse effects include injection site reactions and anaphylaxis (rarely).
Reslizumab (effective for people with high eosinophilia, increased both FEV1 and FVC)
Mepolizumab (decrease number of exacerbations, little effect on FEV1, FeNO)
Benralizumab
• IL-5 primarily affects maturation and differentiation of eosinophils, but can
also affect basophils based on IL-5 receptor α expression.
• Mepolizumab (Nucala®) and Reslizumab (Cinqair®) are “humanized”
monoclonal antibodies that target circulating levels of IL-5. Benralizumab
(Fasenra®) is directed towards IL-5 receptor α.
• Subcutaneous administration lowers levels of circulating eosinophils.
• Adverse effects include injection site reactions and anaphylaxis (rarely).
What is the treatment for mild to moderate asthma
• Bronchodilators are rapidly effective, safe, and inexpensive.
• Patients with only occasional asthma symptoms require no more than an
inhaled SABA (e.g., albuterol) on an “as needed” basis.
• However, additional treatment is needed in any of the following conditions:
a) “rescue” therapy is required >2 times per week
b) nocturnal symptoms occur >2 times per month
c) FEV1 <80%
- First choice would be a low dose of an ICS (e.g., budesonide), but treatment with an oral antileukotriene (e.g., montelukast) may also be used.
- Theophylline is now reserved for patients who respond poorly to other inhaled an/or oral anti-inflammatory agents combined with an as-needed SABA.
What is the treatment for refractory and severe asthma
• In patients whose asthma is poorly controlled by standard doses of ICS (e.g.,
fluticasone), the addition of a LABA (salmeterol or formoterol) has been
shown to be the most effective.
• These combinations are now marketed in single inhalers (e.g., salmeterol + fluticasone, Advair® and formoterol + budesonide, Symbicort®) .
• Patients with chronic severe asthma inadequately controlled by ICS + LABA
combinations are candidates for anti-IgE therapy with omalizumab or anti-IL-5 therapy.
Treatment for acute vs chronic COPD symptoms
Acute COPD Symptoms
Inhalation of a SABA (e.g., albuterol), a SAMRA (e.g., ipratropium), or a
SABA-SAMRA combination (e.g., albuterol-iprotropium) is usually effective.
Chronic COPD Symptoms
For chronic COPD symptoms that limit activities, a LABA (e.g., arformoterol or indacaterol), a LAMRA (e.g., tiotropium or aclidinium), or a corticosteroid-
LABA combination (e.g., fluticasone-vilanterol, Breo®) is indicated.
