Block 2: asthma
Terms
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- describe extrinsic causes of asthma
- caused by environmental factor- usually called allergic asthma becuase patients have pos responses to challenge with specific antigens and inc IgE
- describe intrinsic causes of asthma
- attributed to pathophysiologic disturbances- no family hx, neg response to antigenic challenge, normal IgE
- Is asthma common?
-
yes
more pediatric admissions than any other ds
55% inc from 1982 to 1996 - Early/immediate symptoms of asthma?
-
bronchoconstriciton
vascular leak
HA
proteases
leukotrienes C4 and D4
prostaglandins - Late/sustained symptoms of asthma?
- TH2 cytokines- GM-CSF, IL 3, 4, 5, 9, and 13
- How many asthmatics have identifiable allergies?
-
large percentage of adults don't
50% of kids don't - give examples of precipitants to asthma attacks
-
viral URT infection
exercise/rapid respiration
cold air
chemicals (sulfur dioxide) - What causes airway hyperactivity?
- inflammation of airway mucosa
- acute stage of airway inflammation
- early recruitment of cells to airway
- sub-acute stage of airway inflammation
- recruited and resident cells activated to cause more persistent inflammation
- chronic stage of airway inflammation
- persistent level of cell damage and ongoing repair; permanent abnormalities in airway
- What is of more benefit, drugs that only target bronchoconstriction or drugs that more broadly address inflammation
- drugs that more broadly address inflammation
- What are the two types of asthma drugs
-
short term relievers- relax airway sm mm
long term relievers- anti-inflammatory - Do aerosol treatments work for most patients
- over 90% can be managed by them alone
- this inhaler usually contains a large-column holding chamber (spacer) that fits between the inhaler and mouth; the inhaler discharges into it, and the patient inhales from it
- metered-dose inhaler
- this inhlaer is not as cheap or portable, but doesn't require hand/breathing coordingation
- nebulizer
- this inhaler was developed as an alternative to CFC propellants
- dry powder inhaler
- What is the preferred therapy for bronchoconstriction?
- inhalation beta agonist
- What may regular use of beta agonist inhaler cause?
- potentiate bronchial hyperresponsiveness- tachyphylaxis with diminished beta2 receptors
- MOA of bronchodilators (5)
-
1. relaxes sm mm;
2. inhibits release of bronchoconstricting agents;
3. inhibits microvascular leakage;
4. increases mucociliary transport;
5. beta agonists stimulate adenylyl cyclase --> inc sm mm relax - toxicity from bronchodilators?
-
cardiac arrhythmias from beta-1 stimulation
possible tachyphylaxis or tolerance to beta agonists
*beta2 selectives are usually safe - when can muscarinic antagonists be helpful?
-
when patients are intolerant of inhaled beta agonists;
to enhance nebulized albuterol effect;
role in COPD - what limits the quantity of muscarinic antagonists given
- systemic adverse effects (urinary retintion, tachycardia, loss of accomodation, agitation)
- muscarinic antagonist MOA
- blocks action of ACh from parasympathetic neurons --> blocks bronchoconstriction and icreased secretion of mucous that accompanies vagal activity
- How many asthmatics are tx with methylxanthines
- less than 1%, still used because of high compliance
- methylxanthine MOA
-
antagonism of adenosine receptors --> relaxes bronchial sm mm;
stimulates CNS and cardiac mm; diuretic;
inhibits phosphodiesterases (inc cAMP);
effects Ca conc;
may be anti-inflammatory - side effects of methylxanthines
- arousal, tremor, convulsions, tachycardia, arrythmias, weak diuretic
- how are methylxanthines administered
- are readily absorbed after oral, rectal, and parenteral administration- take your pick
- What is the major drug interaction of methylxanthines
- interacts with many; but major is with macrolide antibiotics- can cause build up of theophylline due to inhibition of P450 --> seizures
- is the TI of methylxanthines high or low?
- low
- give 4 reasons to use corticosteroids
-
1. anti-inflammatory
2. reduces bronchial reactivity and increases airway caliber
3. reduces frequency of asthma attacks
4. potentiates effects of beta agonists - corticosteroid MOA (3)
-
1. inhibits eosinophil-induced inflammation
2. inhibits cytokine production
3. inhibits release of arachidonic acid from cell membranes --> dec prostaglandins and leukotrienes - Adverse effects of inhaled corticosteroids
-
minimal:
cataracts
dec. bone density
oral candidiasis - adverse effects of oral corticosteroids
-
severe:
wt gain
iatrogenic Cushing's syndrome
adrenal suppression - What drugs are used for prophylaxis only?
-
cromolyn and
nedocromil (ne-dOk'-ra-mill) - How are cromolyn and nedocromil used?
- insoluble salts used with inhalers --> plasma conc peaks in 15 minutes --> excreted unchanged
- What types of asthma do cromolyn and nedocromil block?
- antigen and exercise-induced asthma
- What happens when cromolyn and nedocromil are used regularly for more than 2-3 months?
- reduce bronchial hyperactivity
- What's more potent: cromolyn, inhaled glucocorticoids, or nedocromil
- inhaled glucocorticoids > nedocromil > cromolyn
- cromolyn and nedocromil MOA (5)
-
1. inhibit delayed Cl channes
2. reduce mast cell degranulation
3. inhibit release of infl mediators
4. block effects of chemotactic peptides
5. inhibit IgE production - When are leukotriene pathway inhibitors used?
- aspirin or exercise induced asthma
- How are leukotriene pathway inhibitors administered?
- orally
- leukotriene pathway inhibitors MOA
- inhibit synthesis or action --> no LTB4 (neutrophil chemoattractant); LTC4 or LTD4 (bronchoconstriction, reactivity, mucosal edema, and hypersecretion)