COPD and Asthma

Question 1

allergen model of asthma

Answer 1

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

Question 2

chronic inflammation model of asthma

Answer 2

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

Question 3

pathogenesis of COPD

Answer 3

destruction of alveoli, mucus hypersecretion, and fibrosis of small airways

Question 4

beta 2 agonist mechanism

Answer 4

beta 2 agonist goes to receptor and creates cyclic AMP from ATP. this activates PKA, which activates enzymes and calcium channels that bronchodilate

Question 5

effects of beta-2 agonists on airways

Answer 5

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

Question 6

what are the short acting B2 agonists?

Answer 6

albuterol, terbutaline, metoproterenol, pirbutol

Question 7

what is special about levalbuterol?

Answer 7

it is R isomer of albuterol. most beta agonists are racemic mixtures, but only the R isomer exerts beta agonist effects.

Question 8

what are the long acting B2 agonists?

Answer 8

salmeterol, formoterol, indacaterol, vilanterol

Question 9

clinical use of beta 2 agonists

Answer 9

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

Question 10

adverse effects of b2 agonists

Answer 10

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!!

Question 11

tolerance to b2 agonists

Answer 11

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

Question 12

ipratropium vs. tiotropium

Answer 12

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

Question 13

other effects of anti-muscarinic agents

Answer 13

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

Question 14

newer anti-muscarinic agents

Answer 14

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

Question 15

issues with antimuscarinic agents

Answer 15

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

Question 16

clinical uses of anti-muscarinic agents

Answer 16

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

Question 17

mechanism of methylxanthines

Answer 17

prevents conversion of cyclic AMP to AMP

Question 18

methylxanthines effects

Answer 18

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

Question 19

roflumilast

Answer 19

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

Question 20

problems with methylxanthines

Answer 20

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

Question 21

inhaled corticosteroid mechanisms

Answer 21

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

Question 22

clinical use of corticosteroids

Answer 22

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.

Question 23

ciclesonide

Answer 23

a pro-drug. on site activation by esterase. less systemic absorption and side effects.

Question 24

leukotriene inhibitor clinical uses

Answer 24

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.

Question 25

leukotriene inhibitor side effects

Answer 25

well tolerated. liver toxicity. Churg strauss syndrom (may be coincidental)

Question 26

sodium cromoglycate and nedocromil sodium

Answer 26

prevent mast cell degranulation and mediator release from macrophage and eosinophil. molecular mechanism: altered function of delayed chloride channel. alternative medication for mild persistent asthma. side effects are mild and local: cough/through irritation. no role in COPD

Question 27

anti-IgE monoclonal antibody

Answer 27

omalizumab. administered by injection every 2-4 weeks. it reduces the requirement for oral and inhaled corticosteroids and markedly reduces asthma exacerbations. used only in patients with very severe asthma who are poorly controlled on oral orticosteroids