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74 Cards in this Set
- Front
- Back
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What is Asthma?
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A disease of the respiratory system characterized by airways hyperresponsive to stimuli resulting in bronchoconstriction
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4symptoms of Asthma:
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-Wheeze
-Cough -SOB -Tight in chest |
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6 Pathologic effects of Asthma:
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-Decreased airway calibur
-Bronchiolar edema -Increased airway sm muscle contractility -Increased bronchial mucosal secretions -Airway epithelial damage -Airway inflammation |
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How is the severity of asthma measured clinically?
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Via FEV1 - the forced expiratory volume in one second, with a challenge
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What type of challenge is used to measure severity of asthma?
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Methacholine or histamine
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What does a graph of allergen challenge FEV1 vs time show?
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Normal - no change in FEV1
Asthmatic - an early and late phase of decreased FEV1 |
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What receptors on normal airway smooth muscle cells regulate airway calibur?
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-Muscarinic cholinergics
-Adrenergics -NANC |
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What causes bronchoconstriction of airways?
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ACh released by vagus neurons of the parasymp NS acting on muscarinic receptors
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What causes bronchodilation of airways?
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Epi released by the adrenal medulla acting on B2 adrenergic receptors
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What are 5 inflammatory vasoactive substances for which airway smooth muscle cells also have receptors?
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AA metabolites - Leukotrienes, Prostaglandins, Thromboxane
-Histamine -Adenosine |
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What is the response of the airway epithelium to these inflammatory vasoactive substances?
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Some are dilators, some constrictors
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What are the 2 main functions of airway Epithelium?
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-Permeability barrier by removing inhaled particles
-Secrete mucus |
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What regulates epithelial mucus secretion in the airways?
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PNS ACh acting on muscarinic receptors
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What are the 2 barrier functions of the vascular endothelium in the airways?
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-Barrier to fluid flux from blood to the tissue
-Barrier to extravasation of inflammatory cells into lungs |
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What results when the vascular endothelium is leaky?
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Pulmonary edema and possible compromised gas exchange
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What do vascular endothelial cells in the lungs have receptors for?
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Inflammatory vasoactive substances
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What happens during inflammation when these vasoactive substances bind their endothelial receptors?
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-Compromises endothelial barrier function allowing inflammatory cell extravasation into lungs
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What happens upon initial exposure to an allergen?
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The humoral immune system makes anti-allergen IgE which then coats mast cells via IgEr1
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What happens upon subsequent exposure to allergens?
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Allergens bind IgE on mast cells and trigger degranulation
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What prevents exposure to allergen?
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Avoidance
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What drug prevents mast cell degranulation?
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Cromolyn sodium
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What is the result of mast cell degranulation?
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Release of inflammatory mediators: chemokines, leukotrienes, prostaglandins, & bronchoconstrictors.
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What inflammatory cells are recruited by mast cell chemokines?
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Eosinophils, macrophages, and PMNs
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What do the mediators released by mast cells and all the other inflammatory cells do?
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Cause Bronchoconstriction and Inflammation
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What does inflammation in asthma consist of? (3 things)
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-Increased mucus secretion
-Shedding of epithelial cells -Increased capillary permeability |
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What happens when there is chronic inflammation like this?
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Hypersensitivity to the allergen so subsequent exposures result in overkill constriction
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What 4 factors mediate Bronchoconstriction?
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HALT
-Histamine -Adenosine -Leukotrienes -Thromboxane |
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What 5 factors mediate the inflammation?
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PLPCH
Prostaglandins, Leukotrienes, Proteases, Cytokines, Histamine |
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What are the 2 categories of treatment goals for asthma?
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-Bronchodilation
-Anti-inflammation |
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What does bronchodilation achieve?
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Treats the primary symptom of asthma (bronchoconstriction)
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What does reducing inflammation achieve?
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Reduces the hyperresponsiveness of the airway smooth muscle
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What drug is used to inhibit mast cell degranulation?
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Cromolyn sodium
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What does inhibiting mast cell degranulation achieve?
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Prevention of inflammation and bronchoconstriction by preventing mast cell activation
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How does cromolyn sodium prevent mast cell degranulation?
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By preventing transmembrane influx of calcium.
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When must Cromolyn sodium be used for it to be effective in prevent mast cell degranulation?
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Before EXPOSURE to the known asthma trigger.
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What is the main drug type that relaxes bronchial smooth muscle? What else can do it?
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Main: B2 adrenergic agonists
Some: Muscarinic antagonist |
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What are the 2 Beta2 agonists used for treating asthma? How do they differ?
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-Albuterol (short acting)
-Salmeterol (long acting) |
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What allows for Salmeterol to be long acting?
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A long lipophilic tail that embeds into the pm
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Why are B2 agonists like Albuterol and Salmeterol so good?
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Theyre the most effective txmt for bronchoconstriction and provide immediate relief.
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What are the 2 ways that B2 agonists provide relief in asthma?
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-Relax airway smooth muscle
-Stimulate mucociliary transport to get rid of mucus build up |
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What allows for Salmeterol to bind to the plasma membrane?
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A long lipophilic tail binds to an exoreceptor that is near the adrenergic B2 receptor on bronchial smooth muscle.
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What is an unfortunate thing that occurs in using albuterol/salmeterol?
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B2 receptors undergo desensitization which leads to decreased effectiveness of the drugs.
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What are 2 adverse/toxic side effects of B2 agonists like Albuterol and Salmeterol?
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-Overreliance on the drugs
-Cardiac arrythmias |
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Why is overreliance on B2 agonists adverse in asthma patients?
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Because these drugs don't treat the inflammation, just bronchoconstriction, and it may delay their seeking adequete medical care.
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What can't be used to treat hypertension in asthmatics?
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Beta antagonists
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What are 2 other nonadrenergic drugs that relax airway smooth muscle w/ less effectiveness?
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-Methylxanthines
-Anticholinergics |
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What methylxanthine has been used for treating asthma?
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Theophylline - Caffiene
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Why has the importance of Theophylline as a bronchial smooth muscle relaxor waned?
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Because the inhaled B2 agonists are better.
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What are the 2 mechanisms of Theophylline?
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-Inhibits Phosphodiesterase to prolong cAMP action
-Adenosine antagonist |
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Why is inhibition of PDE bad?
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If too much occurs, it stimulates the CNS and cardiovascular system
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What is significant about Theophylline pharmacokinetics?
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It has a very narrow therapeutic window
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What can result if the therapeutic window is exceeded in theophylline treatment?
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Convulsions due to CNS and CV stimulation
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What are 4 signs of Theophylline toxicity?
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-Headache
-Palpitations -Dizziness -Nausea |
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Why aren't cholinergic antagonists used more often for treating asthma?
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Because the SNS is the dominant regulator of the airways in asthmatics, so inhibiting the PNS has little effect.
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What are the cholinergic antagonists? Which one is used for treating asthma sometimes?
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ASI - atropine/scopalamine
IPRATROPIUM BROMIDE |
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What 2 effects can Ipratroprium bromide have on the airways?
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-Bronchial smooth muscle relaxation
-Decreased epithelial mucus secretion |
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2 main pharmacokinetic points about Ipratropium bromide:
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-Quatern. Ammonium - can't penetrate the CNS very well
-Allows for high dose delivery to the airways |
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What is used to treat inflammation in asthma?
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Glucocorticosteroids!!!
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What is the main steroid used for treating asthma? Why?
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Beclomethasone - bc it is the most effective anti-inflammatory drug for treating chronic inflammation underlying asthma
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What is Beclomethasone often used as?
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The first drug for treating newly diagnosed asthma.
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What is beclomethasone NOT effective for?
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Acute asthma attacks
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How long does it take for the effects of beclomethasone to reach maximum?
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A few days
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How does Beclomethasone reduce inflammation in asthma?
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By decreasing the airway hyperresponsiveness by inhibiting production of the inflammatory mediators (LT, PGs, cytokines)
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How exactly does Beclomethasone inhibit the production of the inflammatory mediators?
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By binding a cytosolic steroid receptor, translocating to the nucleus, and binding to transcription factors.
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When Beclomethasone alters transcription, what 2 things are increased and what is decreased?
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Increased: Lipocortin-1 and B2 receptor
Decreased: inflammatory mediators |
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What does Lipocortin-1 do?
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Inhibits phospholipase A2
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What type of steroid administration has to be used for treating severe asthma? Why is this not so pleasant?
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Systemic - has many adverse effects
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What are 3 adverse effects of inhaled steroids?
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-Oropharyngeal candidiasis
-Hoarseness |
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What can directly target inflammatory mediators of bronchoconstriction and inflammation in SOME asthmatics?
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Anti-leukotrienes
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What is the leukotriene receptor antagonist?
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Zafirlukast
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What inhibits 5-lipoxygenase?
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Zileuton
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What type of aspirin are the anti-leukotrienes particularly effective at treating?
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Aspirin-induced asthma
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What are 2 side effects of both Zafirlukast and Zileuton?
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-Liver toxicity
-Interaction with Warfarin resulting in an increased PT |
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What additional adverse side effect does Zileuton have?
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It decreases the steady state concentration of Theophylline.
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