Unit 4 - Asthma/COPD Flashcards
what is the definition of asthma?
clinical syndrome
- chronic inflammation of airways
- recurrent episodes of wheezing, breathlessness, chest tightness, coughing
- variable airway obstruction that is often completely reversible, spontaneously or with treatment
what is the definition of COPD?
disease state
- persistent airway limitation w/ sputum
- progressive (not fully reversible)
- enhanced chronic inflammatory response in airways and lungs to noxious particles and gases
- commonly preventable and treatable, but not usually spontaneously reversible (persistent)
what is active in asthma VS COPD?
- eosinophil or neutrophil?
- T lymphocytes
- B lymphocytes
- response to steroids
- airway obstruction
- risk factors
- natural history
asthma: eosinophils, TH2, IgE producing, responsive to steroids, reversible obstruction, genetic/environmental risk factors, remission possible
COPD: neutrophils, TH1, resistant to steroids, fixed airway obstruction, smoking risk factors, progressive decline
what are bronchodilators and their mechanism?
- inhaled short-acting B2 agonists (albuterol and terbutaline)
- inhaled long-acting B2 agonists (salmeterol and formoterol)
- inhaled anticholinergic (ipratropium bromide and tiotropium bromide)
- slow-release theophylline and aminophylline
what are anti-inflammatory agents and their mechanism?
- inhaled corticosteroids (budesonide, fluticasone propionate, beclomethasone, dipropionate, mometasone
- antileukotrienes (montelukast, zafirlukast, zileuton)
- cromones (sodium cromoglycate and nedocromil sodium)
- anti-immunoglobulin E (omalizumab)
short acting B2 agonist
- names
- onset of action
- peak effect
- duration of action
- mode of delivery
albuterol, terbutaline, metoproterenol, pirbutol
- 5 minute onset of action; peak effect 30-60 minutes; duration of action 4-6 hours
- metered dose inhaler, nebulizer, oral, subcutaneous (terbutaline)
what is the clinical use of short acting B2 agonists?
used as needed basis and during acute exacerbation
- can prevent exercise induced bronchospasm
- mainstay treatment in asthma, but less effective in COPD
what is levalbuterol?
R isomer of albuterol
- most beta agonist are racemic mixtures of R/S, but only R exerts beta effects
- -S isomer causes side effects
- no significant difference in clinical or pharmacological outcome
what are adverse effects of short-acting beta2 agonists
- musculoskeletal tremor
- tachycardia (prolonged QTc)
- hyperglycemia
- hypokalemia, hypomagnesemia
- lactic acidosis
- paradoxical bronchospasm
- tolerance with chronic use (down-regulation of B2 receptor)
long acting B2 agonist
- names
- onset of action
- peak effect
- duration of action
- mode of delivery
salmeterol (partial), formoterol (full), indacaterol (ultra; only COPD)
- 12+ hrs duration of action (S>F)
- 10-30 min (F>S)
- highly lipid soluble and binding to secondary exosite
- always used in combo with inhaled corticosteroids in asthma (CANNOT USE ALONE)
what are side effects of long-acting B2 agonists
- increased respiratory deaths, especially Africans
- -polymorphism in B16 (arg) locus of beta receptor
- salmeterol + corticosteroid failed to show significant difference
antimuscarinic agents
- names
- onset of action
- peak effect
- duration of action
- mode of delivery
- atropine, ipratropium bromide, tiotropium
- M3>M2 affinity
- half life of atropine/ipratropium and bromide is 3.5 hours; tiotropium 34 hours
- bioavailability 25-30% (atropine) or 2-3% (others)
what are clinical uses for tiotropium
anti-inflammatory
-muscarinic receptor found on inflammatory cells
-mast, MP, neutrophils, eosinophils
–reduces neutrophil migration and reduces airway modeling
mucus production/mucociliary clearance
-mucus glands have M3 receptors
-inhibition leads to decrease mucus production
what is Aclidinium bromide? affinity? half life?
newer antimuscarinic agents
- M3>M2 affinity (29 hour half life)
- -extremely short circulation half-life (2.4 minutes)
- less systemic and CNS side effects
- higher dose can be given safely (18 mcg of tiotropium VS 800 mcg aclidinium)
what are side effects of antimuscarnic agents?
- dry mouth, bladder outlet obstruction, acute angle glaucoma, paradoxical bronchospasm (M2 blockade VS additives)
- possible CV mortality and CVA
- inhibition of vagal induced
- receptor selectivity
explain the clinical use of tiotrpoium
antimuscarnic agent
- chronic stable COPD (first line agent)
- chronic asthma (increasing evidence of beneficial effect, but not yet FDA approved)
- not effective in acute exacerbation of asthma and COPD
explain the clinical use of ipratropium bromide
antimuscarinic agent
- chronic COPD - less prefered than tiotropium
- need more frequent dosing
- variable bronchodilator response
- additive effect to nebulized albuterol in acute esvere asthma
- no role in chronic stable asthma
methylxanthines
- names
- mechanism of action
theophylline, theobromine, caffeine
- relatively weaker bronchodilator
- non-selective PDE3/4/5 antagonist (bronchodilation)
- anti-inflammatory (suppression of inflammatory genes by enhancement of histone deacetylation)
- improve contractility and reverse fatigue in diaphragm in COPD
- use waning b/c low therapeutic window
what do methylxanthines have to do with corticosteroids?
methylxanthines restore corticosteroid sensitivity at low doses
what is roflumilast? use? mech?
selective PDE4 inhibitor
- more of an anti-inflammatory (prevents neutrophil migration by inhibiting PDE4 isoforms)
- improvement in lung function secondary to anti-inflammatory action rather than bronchodilation (very weak)
- clinical use approved in COPD
what are problems with methylxanthines?
narrow therapeutic window
-bronchodilation: 10-20 mg/L
-anti-inflammatory: 5-10 mg/L
side effects
-15-20 mg/L: anorexia, nausea, headache, insomnia, GERD
->40 mg/L: cardiac arrhythmia, seizure
-serum level doesn’t correlate with symptoms in chronic users of theophylline
drug interactions
-metabolized by P450, requiring close monotiroing of dose and drug levels
what are corticosteroid effects on inflammatory cells?
T-lymphocytes: decreased cytokine release
-eosinophils: apoptosis decreases numbers
-mast cells: decreased numbers
macrophage: decreased cytokine release
dendritic cell: decreased numbers
what are corticosteroid effects on structural cells?
epithelial cells: decreased cytokines and mediators
endothelial cell: decreased leakiness
airway smooth muscle: increased B2 receptors, decreased cytokines
mucus cells: decreased mucus secretion
describe the clinical use of corticosteroids
- cornerstone treatment of persistent asthma
- limited proven role, but high rate of use in COPD
- -patients with severe disease (FEV1<50%) and frequent exacerbations (can cause pneumonia in high dose or overuse)
- steroid resistant inflammation: COPD, severe asthma, asthmatics who smoke
