Asthma & COPD drugs Flashcards
What is Asthma?
- CHRONIC INFLAMMATORY disorder of the airways
- Characterized by recurring episodes of hyper-responsiveness to stimuli that causes BRONCHOCONSTRICTION (=airflow obstruction)
- Clinical symptoms: recurring episodes of cough, wheezing, tight chest, dyspnea (=shortness of breath)
- Based on the triggering stimuli characterized as EXTRINSIC (allergenic) or INTRINSIC (non-allergenic).
- Reversible airway limitation!
- Except the damage of airway remodeling.
Where is asthma?
Asthma induced changes in airway
- bronchi & bronchioles
What is Extrinsic Asthma?
- MALadaptive immune system response creating memory to allergens.
- External stimuli such as environmental allergens (ie- dust, mold, pollen, animal dander, foods) trigger plasma cells to produce antigen specific IgE antibodies.
- Allergen&IgE binding to mast cells result in degranulation and release of inflammatory mediators.
Allergens have glycoproteins that immune cells recognize as an antigen, substance specific to each allergen. Plasma cells functions as a memory cells producing antibody (IgE) that recognizes only that antigen.
What is Intrinsic Asthma?
- Non-allergenic asthma.
- Symptoms triggered by non allergenic factors
(e.g. anxiety, stress, cold air, dry air, smoke,
exercise, viruses) - The mechanisms initiating the asthma attack are not completely understood, but likely involve:
– Abnormalities in the autonomic regulation of airway functions – increased responsiveness.
– Immune system responses driving bronchoconstriction.
– Mast cells’ degranulation triggered by stimuli other than allergen specific IgE.
What is the acute response of pathophys of Asthma?
-bronchoconstriction
occurs within mins
from mast cells - histamine, leukotrienes, PG’s, PAF
What is the prolonged response?
mast cells & eosinophils & basophil
- vasodilation
- mucus secretion
- edema
- bronchoconstriction
occurs hours after the acute rxns
=> chronic inflammation
What is the airway hyper-responsiveness & remodeling?
- Fibrosis
- Muscle hypertrophy
- Angiogenesis
- Mucus hypersecretion
What is COPD?
= Chronic obstructive pulmonary disease
- Slowly progressive airway obstruction due to CHRONIC INFLAMMATION
- Common in smokers. Other causes: air pollution, occupational exposures and genetics (α1-antitrypsin deficiency ~1%).
- Clinical symptoms: cough, mucus hypersecretion, dyspnea (=shortness of breath)
- This disorders includes CHRONIC BRONCHITIS (inflammation of bronchi) and EMPHYSEMA (destruction of alveolar structure => limited air exchange; CO2 export & O2 import reduced)
- Irreversible airflow limitation!
What is the COPD pathophys?
- Chronic Bronchititis - inflammation & excess mucus
+ Emphysema - alveolar membranes break down
What is Emphysema?
- air exchange becomes difficult in damaged alveoli
- air becomes trapped
What sx’s amenable to drug therapy?
- Excessive airway smooth muscle tone
- Inflammation
- Pulmonary edema
- Mucus plugging
- Cough*
What are drugs divided based on tx strategies?
1) Controllers and 2) Relievers
What are drugs divided based on targets?
1) Airway muscle tone
=> Bronchodilators
(Beta-adrenergic, Methylxanthines, Anticholinergics,
Leukotriene modifiers)
2) Inflammation
=> Anti-inflammatory agents
(Corticosteroids, Mast cell stabilizers, Anti-IgE Monoclonal-Antibody,
Leukotriene modifiers)
What are the bronchodilators?
Agents that interact with smooth muscle cells lining the airways (bronchiole) and relax smooth muscles
- Beta-adrenergic (Albuterol/Salbutamol, Terbutaline, Salmeterol, Formoterol)
- Methylxanthines (Theophylline)
- Anticholinergics (Tiotropium, Ipratropium)
- Leukotriene modifiers (Zileuton, Zafirlukast, Montelukast)
What is Bronchoconstriction?
Activation of parasympathetic nervous system;
Acetylcholine binds to M3 and triggers signaling pathway:
- increased cytoplasmic Ca2+
- Ca2+-calmodulin activates myosin
- myosin binds to actin => actin slide past myosin
=> constriction (that occurs as long as Ca2+ is present)
Adenosine via A1 receptor also increases Ca2+ levels
What is bronchodilation?
Activation of sympathetic nervous system;
noradrenaline/norepinephrine binding to β2 receptor (G-Protein Coupled Receptor), triggers
- Adenylyl cyclase activation, which catalyzes cAMP production
1) promotion of SR Ca2+ pumps
=> decreased cytoplasmic Ca2+
2) prevents activity of enzyme able to activate myosin
=> prevents myosin binding to actin
dilation/relaxation
What is B2-adrenergic Agonists?
Short acting: Albuterol/Salbutamol ”Ventolin”, Terbutaline “Bricanyl”
Long acting (12 hours): Salmeterol ”Serevent”, Formoterol “Foradil”
What is the MOA of B2-adrenergic Agonists?
Stimulate adenylyl cyclase thereby increasing the formation of cAMP which acts to relax the airway smooth muscle leading to bronchodilation.
What is the RofA of B2-adrenergic Agonists?
Typically administered via inhalation
- Albuterol and Terbutaline available in tablet form
- Terbutaline can also be administered subcutaneously
What is the indication of B2-adrenergic Agonists?
- Extensively used in the treatment of Asthma. (1st approach)
- In inhaled form, Albuterol is the drug of choice for the treatment of acute attacks.
- For severe attacks, subcutaneous injection of Terbutaline or Epinephrine (agonist of both α and b adrenergic receptors) may be required.
- Co-administration with corticosteroids/anti-inflammatory drugs recommended to prevent development of desensitization of b2 receptor, and promote efficacy of b2 agonists.
What is the adverse effects of B2-adrenergic Agonists?
- β1 receptors on the heart may get stimulated causing tachycardia.
- Skeletal muscle tremor
- Tolerance may develop with very frequent use.
What are the drug interactions of B2-adrenergic Agonists?
- Not effective on patient taking propranolol for hypertension or other heart/circulatory conditions.
- Co-administration of long term β2 receptor agonists with corticosteroids prevents desensitization.
What is Methyxanthines?
e.g. Theophylline
What is the proposed mech of Methylxanthines?
- Inhibits phosphodiesterase resulting in an increase in cAMP. Reduced cytoplasmic Ca2+ and relaxes the airway.
- Inhibits adenosine receptors; systemic & CNS effects. (Adenosine has been shown to cause the constriction of isolated bronchial smooth muscle and provoke mast cell degranulation.)
- Can stimulate the contractility of diaphragm muscles.
What is the RofA of Theophylline?
Oral (tablets)
What is the indication of Theophylline?
- Used as a second choice for the treatment of acute attacks. However, it has a NARROW therapeutic window and pharmacokinetic slightly unpredictable (vary widely among similar patients) so it should be given under supervision.
- COPD
- May reverse the steroid insensitivity.
What is the adverse effects of Theophylline?
- Common: headache, insomnia, tremors
- Serious: anaphylactic shock; nausea & vomiting, stimulates heart, fever, seizures
- Since it is metabolized by CytoP-450 enzymes, drug interactions may result in toxic concentrations.
- Avoid mixing with foods containing theophylline (e.g. coffee, tea, mate, chocolate).
- Caution: increased cardiovascular effects if given with β2 agonists.
What are the Anticholinergics?
Ipratropium “Atrovent”(short acting)
Tiotropium “Spiriva”(long acting)
What is the MOA of Anticholinergics?
- Blocks muscarinic receptors, preventing bronchial constriction and mucus secretion.
- No effect on inflammation.
