Unit 4 - Asthma/COPD

Question 1

what is the definition of asthma?

Answer 1

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

Question 2

what is the definition of COPD?

Answer 2

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)

Question 3

what is active in asthma VS COPD?

• eosinophil or neutrophil?
• T lymphocytes
• B lymphocytes
• response to steroids
• airway obstruction
• risk factors
• natural history

Answer 3

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

Question 4

what are bronchodilators and their mechanism?

Answer 4

• 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

Question 5

what are anti-inflammatory agents and their mechanism?

Answer 5

• inhaled corticosteroids (budesonide, fluticasone propionate, beclomethasone, dipropionate, mometasone
• antileukotrienes (montelukast, zafirlukast, zileuton)
• cromones (sodium cromoglycate and nedocromil sodium)
• anti-immunoglobulin E (omalizumab)

Question 6

short acting B2 agonist

• names
• onset of action
• peak effect
• duration of action
• mode of delivery

Answer 6

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)

Question 7

what is the clinical use of short acting B2 agonists?

Answer 7

used as needed basis and during acute exacerbation

• can prevent exercise induced bronchospasm
• mainstay treatment in asthma, but less effective in COPD

Question 8

what is levalbuterol?

Answer 8

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

Question 9

what are adverse effects of short-acting beta2 agonists

Answer 9

• musculoskeletal tremor
• tachycardia (prolonged QTc)
• hyperglycemia
• hypokalemia, hypomagnesemia
• lactic acidosis
• paradoxical bronchospasm
• tolerance with chronic use (down-regulation of B2 receptor)

Question 10

long acting B2 agonist

• names
• onset of action
• peak effect
• duration of action
• mode of delivery

Answer 10

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)

Question 11

what are side effects of long-acting B2 agonists

Answer 11

• increased respiratory deaths, especially Africans
• -polymorphism in B16 (arg) locus of beta receptor
• salmeterol + corticosteroid failed to show significant difference

Question 12

antimuscarinic agents

• names
• onset of action
• peak effect
• duration of action
• mode of delivery

Answer 12

• 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)

Question 13

what are clinical uses for tiotropium

Answer 13

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

Question 14

what is Aclidinium bromide? affinity? half life?

Answer 14

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)

Question 15

what are side effects of antimuscarnic agents?

Answer 15

• 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

Question 16

explain the clinical use of tiotrpoium

Answer 16

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

Question 17

explain the clinical use of ipratropium bromide

Answer 17

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

Question 18

methylxanthines

• names
• mechanism of action

Answer 18

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

Question 19

what do methylxanthines have to do with corticosteroids?

Answer 19

methylxanthines restore corticosteroid sensitivity at low doses

Question 20

what is roflumilast? use? mech?

Answer 20

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

Question 21

what are problems with methylxanthines?

Answer 21

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

Question 22

what are corticosteroid effects on inflammatory cells?

Answer 22

T-lymphocytes: decreased cytokine release
-eosinophils: apoptosis decreases numbers
-mast cells: decreased numbers
macrophage: decreased cytokine release
dendritic cell: decreased numbers

Question 23

what are corticosteroid effects on structural cells?

Answer 23

epithelial cells: decreased cytokines and mediators
endothelial cell: decreased leakiness
airway smooth muscle: increased B2 receptors, decreased cytokines
mucus cells: decreased mucus secretion

Question 24

describe the clinical use of corticosteroids

Answer 24

• 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

Question 25

what can steroid sensitivity be restored by?

Answer 25

low doses of theophylline

Question 26

what is the relationship between corticosteroids and B2 agonists?

Answer 26

beneficial combo with B2 agonist (increases B2 receptor gene transcription –> B2 increases translocation of corticosteroid receptor from cytoplasm to nucleus

Question 27

what is ciclesonide?

Answer 27

corticosteroid prodrug with on-site acctivation by esterase

• less systemic absorption
• less systemic side effects

Question 28

explain the formulation of metered dose inhalers?

Answer 28

propellant-based (HFA/CFC = hydrofluoralkane/chlorofluorocarbon)

• solution or suspension
• machine actuated
• needs actuation - inhalation coordination
• slow inspiratory flow rate (mostly < 60 L/min)

Question 29

explain the formulation of dry powder inhalers?

Answer 29

non-propellant based

• solid particles
• patient actuated (patient controls it)
• faster inspiratory flow rate (usually > 60 L/min)

Question 30

what are leukotriene inhibitors and where do they act?

Answer 30

5-lipoxygenase inhibitors: zileuton

LT-antagonists: montelukast, pranlukast, zafirlukast

Question 31

what are leukotriene inhibitor clinical uses?

Answer 31

• add-on therapy in mild asthma
• less effective than doubling dose of inhaled corticosteroid or adding B2 agonist
• drug of choice for aspirin-induced asthma
• can be given in oral tablet
• prophylaxis for exercise-induced bronchospasm
• no role in COPD

Question 32

what are side effects of leukotriene inhibitors?

Answer 32

• liver toxicity (zileuton)
• Churg-Strauss syndrome (may be coincidental)
• well tolerated

Question 33

what is sodium cromoglycate and nedocromil sodium? mech? use?

Answer 33

prevent mast cell degranulation and emdiator release from macrophage and eosinophils

• molecular mech: altered function of delayed chloride channel
• alternative, not preferred, medications for treatment of mild persistent asthma
• used as preventive treatment before exercise or unavoidable exposure to known allergens
• no role in COPD

Question 34

what are side effects of Na cromoglycate and nedocromil Na?

Answer 34

mild and local cough and throat irritation

Question 35

what is omalizumab?

Answer 35

anti-IgE monoclonal Ab

• administered by subcutaneous injection every 2-4 weeks
• reduces requirement for oral and inhaled corticosteroids and markedly reduces asthma exacerbations
• only used if very severe asthma and poorly controlled on oral corticosteroids

Question 36

describe intermittent asthma

• symptoms
• nighttime awakenings
• short-acting B2 use for symptom control
• interference w/ normal activity
• lung function
• risk
• recommended initial treatment

Answer 36

80%, FEV1/FVC normal)

• risk 0-1 year
• initial step 1 treatment

Question 37

describe mild persistent asthma

• symptoms
• nighttime awakenings
• short-acting B2 use for symptom control
• interference w/ normal activity
• lung function
• risk
• recommended initial treatment

Answer 37

• > 2 days/week but not daily
• 3-4x/mo
• > 2 days/wk but not daily, and not more than 1x/day
• minor limitation
• FEV >80%, FEV/FVC normal
• risk >2/yr
• initial Step 2 treatment

Question 38

describe moderate persistent asthma

• symptoms
• nighttime awakenings
• short-acting B2 use for symptom control
• interference w/ normal activity
• lung function
• risk
• recommended initial treatment

Answer 38

• daily attacks
• > 1x/wk but not nightly
• daily use
• some limitation
• FEV1>60%, but 2/yr
• initial step 3 and consider short course of oral systemic corticosteroids

Question 39

describe severe persistent asthma

• symptoms
• nighttime awakenings
• short-acting B2 use for symptom control
• interference w/ normal activity
• lung function
• risk
• recommended initial treatment

Answer 39

• attacks throughout day
• often 7x/wk
• several times/day
• extremely limited
• FEV15%
• risk >2/yr
• initial step 4/5 and consider short course of oral systemic corticosteroids

Question 40

what is the usual treatment course of action for asthma and COPD?

Answer 40

differences between COPD and asthma disappear during exacerbations

• systemic corticosteroid for short period (5-7 days)
• short acting B2 agonist and short acting anticholinergic via nebulizer (albuterol, ipratropium)
• antibiotics usually prescribed in exacerbation of COPD
• no role of long-acting B2 agonist or long-acting anticholinergic

Question 41

what drugs are related to CYP 450?

Answer 41

montelukast, salmetrol, budesonide, theophylline