COPD and Asthma Flashcards
allergen model of asthma
exposure to allergen causes synthesis of IgE, which binds to mast cells in the airway mucosa. On reexposure to allergen, antigen-antibody interaction on mast cell surfaces triggers release of mediators of anaphylaxis: histamine, trpytase, prostaglandin D2, Leukotriene C4, and platelet activating factor. these provoke contraction of airway smooth muscle
chronic inflammation model of asthma
frequent exposure to allergens leads to inflammatory cells being recruited / activated in the airways, which release a variety of inflammatory mediators that have acute effects on the airway (bronchoconstriction, plasma leakage, vasodilation, mucus secretion, etc) along with structural changes that include subepithelial fibrosis, increased numbers of blood vessels and mucus secreting cells, and increased thickness of airway smooth muscle
pathogenesis of COPD
destruction of alveoli, mucus hypersecretion, and fibrosis of small airways
beta 2 agonist mechanism
beta 2 agonist goes to receptor and creates cyclic AMP from ATP. this activates PKA, which activates enzymes and calcium channels that bronchodilate
effects of beta-2 agonists on airways
prevention of mediator release from mast cells. prevention of microvascular leakage and edema. increased mucus secretion and ion transport. reduced cholinergic neurotransmission. modification of acute inflamm, no effect on chronic inflamm
what are the short acting B2 agonists?
albuterol, terbutaline, metoproterenol, pirbutol
what is special about levalbuterol?
it is R isomer of albuterol. most beta agonists are racemic mixtures, but only the R isomer exerts beta agonist effects.
what are the long acting B2 agonists?
salmeterol, formoterol, indacaterol, vilanterol
clinical use of beta 2 agonists
mainstay in treatment of asthma. short acting agents prevent acute exacerbations and exercise induced bronchospasm. can worsen asthma if used frequently in high doses. long acting agents allow long term control of symptoms especially nocturnal symptoms. always used in combo with inhaled steroids
adverse effects of b2 agonists
due to lost selectivity at high doses. musculoskeletal tremor, tachycardia/palpitations, prolonged QTc, hypokalemia, V/Q mismatch, metabolic effects (hypomagnesaemia, hyperglycemia, lactic acidosis). Trials show to only use in combo with corticosteroids!!
tolerance to b2 agonists
tolerance to airway bronchodilating response has not been found in asthma. tolerance readily develops to non airway b2 receptor mediated response. tolerance develops to bronchoprotective effects of b2 agonists on exercise and allergen induced bronchoconstriction
ipratropium vs. tiotropium
ipra is short acting (2-5 hr duration), metabolized to inactive esters. Tio is long acting (24+ hr duration) and is metabolized in the liver
other effects of anti-muscarinic agents
anti-inflamm: muscarinic receptor is found on inflamm cells. tiotrop reduces neutrophil migration and airway remodeling. Mucus production/mucociliary clearance: mucus glands have M3 receptors, and inhibition leads to decreased mucus production
newer anti-muscarinic agents
aclidinium bromide. high dose can be given safely. short half life circulation (2-4 min). structurally and functionally similar to tiotrop, M3 affinity preferred. less systemic and CNS side effects
issues with antimuscarinic agents
side effects: dry mouth, bladder problems, acute angle glaucoma, bronchospasm.
Effective dosing: inhibition of vagal induced bronchoconstriction requires higher dose than currently used therapeutic doses.
Receptor selectivity: the more M3 selectivity the better
clinical uses of anti-muscarinic agents
tiotrop: chronic stable COPD first line agent. chronic asthma. not effective in acute asthma or COPD.
Ipratropium: chronic COPD (less preffered than tiotrop). need more freq dosing. variable bronchodilator response. additive effect to nebulized albuterol in acute asthma. no role in chronic stable asthma
mechanism of methylxanthines
prevents conversion of cyclic AMP to AMP
methylxanthines effects
relatively weak bronchodilator. anti-inflamm (suppresses inflamm genes). improves contractility and reverses fatigue of diaphragm. antagonism of adenosine receptor reduces apoptosis. Restores corticosteroid sensitivity. low therapeutic window
roflumilast
selective PDE4 inhibitor. more of an anti-inflamm agent. prevents neutrophil migration by inhibiting PDE4 isoforms. Improvement in lung function is secondary to anti-inflamm action, rather than bronchodilation. approved in COPD
problems with methylxanthines
narrow therapeutic window. side effects: anorexia, nausea, headache, GERD at low dose. Cardiac arrhythmia and seizure at high dose. Drug interactions: metabolized by P450 enzymes, be careful with drugs that activate or inhibit P450
inhaled corticosteroid mechanisms
activation of anti-inflamm genes, suppression of pro-inflamm genes. reduces bronchial hyper-responsiveness by suppressing inflammation. no effect on contractile response. no effect on the early response to allergen but inhibit late response. increase airway response to b2 agonist. reduces vascular permeability and airway edema
clinical use of corticosteroids
first line therapy for persistent asthma. limited proven role but high rate of use in COPD. use only in patients with severe disease and frequent exacerbations. may cause pneumonia. beneficial combination with b2 agonist. increases transcription of b2 receptor gene.
ciclesonide
a pro-drug. on site activation by esterase. less systemic absorption and side effects.
leukotriene inhibitor clinical uses
used as add on therapy in mild asthma. less effective than doubling dose of inhaled corticosteroid or adding beta 2 agonist. drug of choice for aspirin induced asthma. prophylaxis for exercise induced bronchospasm. no role in COPD.
