Module 3: Drugs for Asthma + COPD Flashcards
Asthma Pathophysiology from Drug POV
Symptoms of asthma result from a combination
of inflammation and bronchoconstriction, so
treatment must address both components
COPD Pathophysiology from Drug POV
Symptoms of COPD result largely from two
pathologic processes: Chronic bronchitis and
emphysema
Both processes are caused by an exaggerated
inflammatory reaction to cigarette smoke
Chronic bronchitis, which is defined by a chronic
cough and excessive sputum production, results
from hypertrophy of mucus-secreting glands in
the epithelium of the larger airways
Overview of Drugs for
Asthma and COPD
Two main pharmacologic classes
Anti-inflammatory agents
* Glucocorticoids (prednisone)
Bronchodilators
* Beta2 agonists (albuterol)
Inhalation Drug Therapy
Three obvious advantages
Therapeutic effects are enhanced
Systemic effects are minimized
Relief of acute attacks is rapid
Three types
Metered-dose inhalers (MDIs)
Respimats
Dry-powder inhalers (DPIs)
Nebulizers
Anti-inflammatory Drugs
Foundation of asthma therapy
Taken daily for long-term control
Principal anti-inflammatory drugs are the
glucocorticoids (eg, budesonide, fluticasone)
Anti-inflammatory Drugs:
Glucocorticoids
Mechanism of action
Considered the most effective antiasthma drugs
available
Decrease synthesis and release of inflammatory
mediators
Reduce infiltration and activity of inflammatory cells
Decrease edema of the airway mucosa caused by
beta2 agonists
Usually administered by inhalation, but IV and
oral routes are also options
Mechanism of action = suppress inflammation
Reduce bronchial hyperreactivity and decrease
airway mucous production
May increase the number of bronchial beta2
receptors and their responsiveness to beta2
agonists
Use
Prophylaxis of chronic asthma
Dosing must be on a fixed schedule, not as needed
(PRN)
Not used to abort an ongoing attack because
beneficial effects develop slowly
Inhaled use
First-line therapy for management of inflammatory
component of asthma
Most patients with persistent asthma should use
these drugs daily
Inhaled glucocorticoids are very effective and much
safer than systemic glucocorticoids
Oral use
For patients with moderate to severe persistent
asthma or for management of acute exacerbations of
asthma or COPD
Potential for toxicity; should be used only when
symptoms cannot be controlled with safer
medications (inhaled glucocorticoids, inhaled beta2
agonists)
Treatment should be as brief as possible
Anti-inflammatory Drugs:
Glucocorticoids
Adverse Effects of Inhaled Forms
Adverse effects of inhaled forms
Adrenal suppression
Mechanism: Corticosteroids can suppress the hypothalamic-pituitary-adrenal (HPA) axis, leading to reduced production of natural cortisol by the adrenal glands. This is more likely with higher doses of inhaled corticosteroids.
Implications: In situations of stress, such as surgery or severe illness, patients with adrenal suppression may require supplemental systemic corticosteroids to prevent adrenal crisis.
Oropharyngeal candidiasis
Description: Also known as oral thrush, this is a fungal infection caused by Candida species, commonly Candida albicans. The inhaled corticosteroid can disrupt the normal oral flora balance and depress local immune responses, creating an environment conducive to fungal overgrowth.
Prevention and Management: Rinsing the mouth with water and spitting it out after each inhalation can help reduce the risk. Antifungal treatments, such as nystatin or fluconazole, may be needed if an infection develops.
Dysphonia
Description: Dysphonia refers to difficulty speaking or changes in the voice, such as hoarseness. Inhaled corticosteroids can cause irritation and myopathy of the laryngeal muscles, leading to voice changes.
Management: Techniques such as using a spacer device with metered-dose inhalers, improving inhalation technique, and reducing the dose of inhaled corticosteroids (while maintaining asthma control) can help minimize this effect. Voice rest and hydration may also be beneficial.
Glucocorticoids can slow growth in children and
adolescents; however, these drugs do not decrease
adult height
Promotion of bone loss
Increased risk of cataracts
Increased risk of glaucoma
Anti-inflammatory Drugs:
Glucocorticoids
Adverse Effects of Oral Forms
Adverse effects of oral forms
Short-term therapy
Long-term therapy
Adrenal suppression
Osteoporosis
Hyperglycemia
Peptic ulcer disease
In young patients: Growth suppression initially, but
does not impact final adult height
Adrenal suppression
Prolonged glucocorticoid use can decrease the ability of the adrenal cortex to produce glucocorticoids of its own
Life-threatening at times of severe physiologic stress (eg, surgery, trauma, or systemic infection)
High levels of glucocorticoids are required to survive severe stress
Adrenal suppression prevents production of endogenous glucocorticoids
Patients must be given increased doses of oral or IV
glucocorticoids at times of stress
Failure to do so can prove fatal
D/C Gluticosteroid Treatment
Discontinuing treatment
* Must be done slowly
* Recovery of adrenocortical function takes several months
* Dosage of exogenous sources must be reduced gradually
* During this time, patients—including those switched to
inhaled glucocorticoids—must be given supplemental oral or IV glucocorticoids at times of severe stress
Anti-inflammatory Drugs:
Leukotriene Receptor Antagonists
Suppress effects of leukotrienes
Leukotrienes: Promote smooth muscle constriction,
blood vessel permeability, and inflammatory
responses through direct action and recruitment of
eosinophils and other inflammatory cells
In patients with asthma, leukotriene modifiers
can reduce bronchoconstriction and
inflammatory responses such as edema and
mucous secretion
Second-line agents
Generally well tolerated but can cause adverse
neuropsychiatric effects, including depression,
suicidal thinking, and suicidal behavior
Available agents
Zileuton [Zyflo]
Zafirlukast [Accolate]
Montelukast [Singulair
Zileuton [Zyflo]
Mechanism of Action
Leukotriene Inhibition: Zileuton works by inhibiting 5-lipoxygenase, an enzyme that is crucial in the leukotriene synthesis pathway. By blocking this enzyme, zileuton prevents the formation of leukotrienes, such as leukotriene B4 (LTB4), which is involved in inflammatory responses, and cysteinyl leukotrienes (LTC4, LTD4, LTE4), which are potent bronchoconstrictors and contribute to the pathophysiology of asthma.
Effect on Asthma: By reducing leukotriene production, zileuton decreases inflammation, bronchoconstriction, and mucus secretion in the airways, leading to improved asthma symptoms and lung function.
Adverse Effects
While zileuton can be effective in managing asthma, it can also have several adverse effects, some of which include:
Liver Enzyme Elevations: One of the most significant concerns with zileuton is its potential to cause liver injury. It can increase liver enzymes, indicating liver stress or damage. Patients taking zileuton require regular monitoring of liver function tests before and during treatment to detect any liver injury early.
Nausea and Dyspepsia: Gastrointestinal disturbances such as nausea, dyspepsia (indigestion), and abdominal pain can occur in patients taking zileuton.
Headache: Some patients may experience headaches while on zileuton therapy.
Neuropsychiatric Events: Although less common, neuropsychiatric events such as sleep disturbances, depression, and anxiety have been reported in patients taking leukotriene modifiers, including zileuton.
Given the potential for liver toxicity and other adverse effects, the use of zileuton is generally reserved for patients whose asthma is not adequately controlled with other medications, and who can adhere to the required monitoring. The decision to use zileuton should involve a careful assessment of the benefits and risks, considering the individual patient’s asthma severity, comorbid conditions, and response to other asthma therapies.
Montelukast [Singulair]
Mechanism of Action
Leukotriene Receptor Blockade: Montelukast works by selectively blocking leukotriene receptors, specifically the cysteinyl leukotriene type 1 (CysLT1) receptors found in the lungs and airways. Cysteinyl leukotrienes (LTC4, LTD4, LTE4) are potent inflammatory mediators produced by cells in the lungs, including mast cells and eosinophils, and are involved in the pathophysiology of asthma and allergic rhinitis.
Effect on Asthma and Allergies: By blocking the action of cysteinyl leukotrienes, montelukast reduces bronchoconstriction, airway inflammation, and mucus production, leading to improved control of asthma symptoms. It also reduces nasal congestion, sneezing, and itching in allergic rhinitis.
Adverse Effects
Montelukast is generally well-tolerated, but some individuals may experience side effects, including:
Psychiatric Events: There have been reports of neuropsychiatric events in patients taking montelukast, including mood changes, depression, suicidal thoughts or actions, agitation, aggressive behavior, hallucinations, and sleep disturbances. The U.S. Food and Drug Administration (FDA) has issued warnings about these potential risks, and patients and caregivers are advised to be alert to changes in behavior or mood.
Respiratory Symptoms: Although used to treat asthma, montelukast can sometimes cause or worsen respiratory symptoms like cough, wheezing, or shortness of breath in some individuals.
Gastrointestinal Issues: Some people may experience stomach pain, diarrhea, indigestion, or nausea.
Headaches: Headaches are among the more common side effects reported by patients taking montelukast.
Given the potential for neuropsychiatric side effects, healthcare providers are advised to weigh the risks and benefits of prescribing montelukast, particularly for mild conditions not adequately controlled by other treatments. Patients and caregivers should be informed about the signs and symptoms of potential psychiatric events. Montelukast is typically used when other treatments, such as inhaled corticosteroids for asthma, have not provided adequate control of symptoms, or in cases where patients have concurrent asthma and allergic rhinitis.
Mast Cell Stabilizer:
Cromolyn
Used for prophylaxis, not for quick relief
Suppresses inflammation; not a bronchodilator
Mechanism of action: Stabilizes cytoplasmic
membrane of mast cells, thereby preventing
release of histamine and other mediators; in
addition, inhibits eosinophils, macrophages, and
other inflammatory cells
Route: Inhalation
Nebulizer
Therapeutic use
Chronic asthma
Exercise-induced bronchospasm (EIB)
Allergic rhinitis
Adverse effects
Safest of all antiasthma medications
Cough
Bronchospasm
Monoclonal Antibody:
Omalizumab [Xolair]
Mechanism of action
Antagonism of immunoglobulin E (IgE), a type of
antibody
Therapeutic use
Patients age 12 years or older with moderate to
severe asthma that (1) is allergy related and (2)
cannot be controlled with an inhaled glucocorticoid
Adverse effects
Injection-site reactions
Viral infection
Upper respiratory infection
Sinusitis
Headache
Pharyngitis
Cardiovascular events
Malignancy
Life-threatening anaphylaxis
Interleukin-5 Receptor Antagonists: Benralizumab, Mepolizumab, Reslizumab
Benralizumab, mepolizumab, and reslizumab are monoclonal antibodies targeting the interleukin-5 (IL-5) pathway, which plays a crucial role in the maturation, activation, and survival of eosinophils.
Eosinophils are a type of white blood cell involved in the inflammatory process of certain types of asthma, particularly eosinophilic asthma, which is characterized by high levels of eosinophils in the blood, tissue, and sputum. These medications are part of a class known as interleukin-5 receptor antagonists and are used as add-on maintenance treatments for severe eosinophilic asthma in adults and some pediatric populations.
Actions and Uses
Benralizumab (Fasenra): Targets the IL-5 receptor alpha on eosinophils and basophils, leading to direct cell apoptosis (cell death). It is administered via subcutaneous injection.
Mepolizumab (Nucala): Binds to IL-5 itself, preventing it from interacting with its receptor on eosinophils. It reduces blood, tissue, and sputum eosinophil levels and is administered via subcutaneous injection.
Reslizumab (Cinqair): Also binds directly to IL-5, inhibiting its activity. It is indicated for intravenous use.
These agents are used in individuals with severe asthma that is not well controlled with standard treatments such as high-dose inhaled corticosteroids and long-acting beta-agonists. By targeting IL-5, they effectively reduce eosinophil counts, leading to fewer asthma exacerbations, improved lung function, and better asthma control.
Adverse Effects
Injection Site Reactions: Pain, erythema, and swelling at the injection site are common for subcutaneously administered drugs (benralizumab and mepolizumab).
Hypersensitivity Reactions: Although rare, hypersensitivity reactions, including anaphylaxis, can occur following administration of these medications.
Headache: A frequently reported side effect.
Respiratory Infections: There is an increased risk of common respiratory infections, such as nasopharyngitis and bronchitis.
Herpes Zoster: Some patients may have an increased risk of developing herpes zoster (shingles) while on these treatments.
Contraindications
Hypersensitivity: The primary contraindication for benralizumab, mepolizumab, and reslizumab is a known hypersensitivity to the active substance or any of the excipients. Patients with a history of hypersensitivity reactions to these drugs should not receive them.
**for severe asthma
Dupilumab
Dupilumab is a monoclonal antibody that targets the interleukin-4 (IL-4) and interleukin-13 (IL-13) pathways, which are key drivers of Type 2 inflammation in various allergic diseases, including asthma, atopic dermatitis (eczema), and chronic rhinosinusitis with nasal polyps. It is important to note that dupilumab is not an interleukin-5 (IL-5) receptor antagonist, so it does not directly target the IL-5 pathway involved in eosinophil maturation and activation. Instead, it works by blocking the shared receptor component for IL-4 and IL-13, thus inhibiting the signaling of both these cytokines.
Actions and Uses
Asthma: Dupilumab is used as an add-on maintenance treatment for severe asthma characterized by an eosinophilic phenotype or with oral corticosteroid-dependent asthma. It helps reduce severe asthma attacks and improve lung function.
Atopic Dermatitis: For moderate-to-severe atopic dermatitis that is not adequately controlled with topical prescription therapies, dupilumab can significantly reduce skin inflammation and itching.
Chronic Rhinosinusitis with Nasal Polyps: It helps reduce nasal polyp size, nasal congestion severity, and the need for systemic corticosteroids or surgery.
Dupilumab is administered via subcutaneous injection.
Adverse Effects
Injection Site Reactions: Pain, redness, and swelling at the injection site are common.
Eye Issues: Conjunctivitis, keratitis, and other eye-related inflammations can occur, particularly in patients with atopic dermatitis.
Eosinophilia: An increase in eosinophil count can happen and may be associated with systemic eosinophilia in rare cases.
Hypersensitivity Reactions: Includes rare cases of serious hypersensitivity reactions, such as anaphylaxis.
Skin Reactions: Some patients may develop skin reactions near the injection site or eczema herpeticum.
Contraindications
Hypersensitivity: The primary contraindication for dupilumab is a history of severe hypersensitivity reactions to dupilumab or any of its excipients. Patients known to be hypersensitive to the drug should not receive it.
Phosphodiesterase-4 Inhibitor: Roflumilast
Roflumilast is a medication classified as a selective phosphodiesterase-4 (PDE-4) inhibitor. It is primarily used in the treatment of severe chronic obstructive pulmonary disease (COPD) to reduce the frequency of exacerbations in patients with a chronic bronchitis phenotype and a history of exacerbations.
Mechanism of Action
PDE-4 Inhibition: Roflumilast exerts its therapeutic effects by selectively inhibiting the enzyme phosphodiesterase-4 (PDE-4), which is predominantly found in lung tissue, immune cells, and pro-inflammatory cells. By inhibiting PDE-4, roflumilast leads to an increase in intracellular levels of cyclic adenosine monophosphate (cAMP).
Anti-inflammatory Effects: The increased cAMP levels result in a broad range of anti-inflammatory effects, including the suppression of cytokine release and the reduction of immune cell activation and infiltration in the lungs. This leads to a decrease in the inflammation that is characteristic of COPD.
Therapeutic Use
COPD Management: Roflumilast is specifically indicated for reducing the risk of COPD exacerbations in patients with severe COPD associated with chronic bronchitis and a history of exacerbations. It is generally used as an add-on therapy to bronchodilators and is not intended for the relief of acute bronchospasm.
Pharmacokinetics
Absorption: Roflumilast is well absorbed after oral administration, with peak plasma concentrations reached within approximately 1 hour.
Metabolism: It is extensively metabolized in the liver, primarily via the cytochrome P450 (CYP) 1A2 and 3A4 pathways, to its active metabolite, roflumilast N-oxide, which also contributes to the drug’s therapeutic effect.
Elimination: The drug and its metabolites are primarily excreted in the urine. The elimination half-life of roflumilast and its N-oxide metabolite is approximately 17 and 30 hours, respectively, allowing for once-daily dosing.
Adverse Effects
Gastrointestinal Symptoms: Diarrhea, weight loss, nausea, and abdominal pain are among the most common side effects.
Psychiatric Symptoms: Roflumilast can be associated with insomnia, anxiety, and depression. Patients should be monitored for the emergence of psychiatric symptoms.
Weight Loss: Significant weight loss can occur, and patients’ weight should be monitored regularly during treatment.
Headache: Some patients may experience headaches.
Bronchodilators
Provide symptomatic relief but do not alter the
underlying disease process (inflammation)
In almost all cases, patients taking a
bronchodilator should also be taking a
glucocorticoid for long-term suppression of
inflammation
Principal bronchodilators are the beta2-
adrenergic agonists
Bronchodilators:
Beta2-Adrenergic Agonists
Mechanism of action
Through activation of beta2 receptors in the smooth
muscle of the lung, these drugs promote
bronchodilation, relieving bronchospasm
Beta2 agonists have a limited role in suppressing
histamine release in the lung and increasing ciliary
motility
Use in asthma and COPD
Inhaled short-acting beta2 agonists (SABAs)
* Taken PRN to abort an ongoing attack
* EIB: Taken before exercise to prevent an attack
* Hospitalized patients undergoing a severe acute attack: Nebulized SABA is the traditional treatment of choice
* Delivery with an MDI in the outpatient setting may be equally effective
Inhaled long-acting beta2 agonists (LABAs)
* Long-term control in patients who experience frequent
attacks
* Dosing is on a fixed schedule, not PRN
* Effective in treating stable COPD
* When used to treat asthma, must always be combined with a glucocorticoid
* Use alone in asthma is contraindicated
Adverse effects
Inhaled preparations
* Systemic effects: Tachycardia, angina, tremor
Oral preparations
* Excessive dosage: Angina pectoris, tachydysrhythmias
* Tremor
Bronchodilators:
Methylxanthines
Theophylline
Other methylxanthines include aminophylline
and dyphylline
Theophylline
Produces bronchodilation by relaxing smooth muscle
of the bronchi
Narrow therapeutic index
Plasma level 10 to 20 mcg/mL
Toxicity is related to theophylline levels
The drug is usually administered by mouth but
may also be administered intravenously
Use in asthma and COPD
Oral theophylline is used for maintenance therapy of chronic stable asthma
Theophylline is no longer recommended for treatment of COPD
Toxicity
Plasma levels below 20 mcg/mL: Adverse effects uncommon
Plasma levels of 20 to 25 mcg/mL: Nausea, vomiting,
diarrhea, insomnia, restlessness
Plasma levels above 30 mcg/mL: Severe dysrhythmias (eg, ventricular fibrillation) and convulsions
Death may result from cardiorespiratory collapse
Toxicity treatment
Stop theophylline
Activated charcoal together with a cathartic
Dysrhythmias respond to lidocaine
Intravenous diazepam may help control seizures
Interactions
Caffeine
Tobacco and marijuana
Cimetidine
Fluoroquinolone antibiotic
Anticholinergic Drugs:
Ipratropium
Improves lung function by blocking muscarinic receptors in the bronchi, thereby reducing bronchoconstriction
Action and use
Administered by inhalation to relieve bronchospasm
Therapeutic effects begin within 30 seconds, reach 50% of maximum in 3 minutes, and persist about 6 hours
Adverse effects
Dry mouth and irritation of the pharynx
Glaucoma
Cardiovascular events
Anticholinergic Drugs:
Tiotropium
Long-acting, inhaled anticholinergic agent approved for
maintenance therapy of bronchospasm associated with
COPD
Not approved for asthma
Relieves bronchospasm by blocking muscarinic
receptors in the lung
Therapeutic effects begin about 30 minutes after
inhalation, peak in 3 hours, and persist about 24 hours
With subsequent doses: Bronchodilation continues to
improve, reaching a plateau after eight consecutive
doses (8 days)
Adverse effect: Dry mouth
Minimal anticholinergic effects
Anticholinergic Drugs:
Aclidinium
Newest long-acting anticholinergic for
management of bronchospasm associated with
COPD
Relieves bronchospasm by blocking muscarinic
receptors in the lung
Peak levels have occurred within 10 minutes of
drug delivery
Intended only for maintenance therapy
Not for acute symptom relief
Adverse effects
Headache
Nasopharyngitis
Cough
