PBL CASE #3: FACULTY LEARNING ISSUES
1.
(1)
Describe the physiology and physics of airway resistance. Evaluate the
respiratory work necessary to overcome airway resistance. Be sure you
understand dynamic compression of airways.
AIRWAY RESISTANCE
 As air flows through a tube, a difference in pressure exists between the ends
and depends on the rate and pattern of flow.
o Laminar flow: low flow rates, the stream lines are parallel to the sides
of the tube
 The radius is of critical important when determining the
resistance to flow through a tube
o Transitional flow: as flow rate increases, unsteadiness develops,
especially at branch points
o Turbulent flow: at higher flow rate, complete disorganization occurs .
 In rapidly branching systems like the lungs, fully developed laminar flow likely
only occurs in very small airways where the Re umbers are low.
 In most of the bronchial tree, the flow is transitional
 The major site of resistance in the medium sized bronchi
o The very small bronchioles contribute relatively little resistance which
is due to the vast number of small airways
 Factors determining airways resistance
o Lung volume: as lung volume is reduced, airway resistance rise rapidly
 At low lung volumes, the small airways may close completely
o Contraction of bronchial smooth muscle narrows airways and increases
airways resistance
 May occur via reflexes (smoke)
 Stimulation of adrenergic receptors causes
bronchodilation
 Parasympathetic activity causes bronchoconstriction
(ACh)
o Decreased PCO2 in alveolar gas causes an increase in airway resistance,
as a direct action on bronchiolar smooth muscle
o Histamine causes pulmonary artery constriction
o Density and viscosity of gas affect resistance to flow
 Resistance in increased during a deep dive because the
increases pressure raises gas density
 Reduced pressure when a helium-O2 mixture is breathed
 Dynamic Compression Airways
Before inspiration has begun, airway
pressure is zero everywhere. Because
interpleural pressure is -5 cm H2O, there
is a pressure of 5 cm H2O holding the
airway open
As inspiration begins, both
intrapleural and alveolar pressure
fall by 2 cm H2O and flow beings.
Because of the pressure drop along
the airway, the pressure inside is -1
cm H2O
In each of the situations, the
descending portion of the curve takes
the same path, suggesting that
something is limiting expiratory flow.
 dynamic compression of airway
resistance
Work required to
overcome elastic
forces
Work overcoming
the airway/tissue
resistance
During inspiration, the intrapleural
pressure follows the curve A  B 
C (work done by lung is the area
0ABCD0)
0ABCD0 = total work done by lung
At end of inspiration, flow is zero
and there is an airway transmural
pressure of 8 cm H2O
At the start of forced expiration,
both intrapleural pressure and
alveolar pressure increased by
38 cm H2O. Because of the
pressure drop along the airway
as flow beings, there is now a
pressure 11 cm H2O and this
closed the airway. Airway
compression occurs and the
downstream pressure limiting
flow becomes the pressure
outside the airway
PBL CASE #3: FACULTY LEARNING ISSUES
2.
A patient with asthma has an attack that results in bronchoconstriction to one
lung lobe (drastically reducing its ventilation). Determine how this effects the
VA/Q (ventilation –perfusion ratio) in that lobe and how does this effect the
partial pressures of oxygen and carbon dioxide in the blood leaving that lobe
and in the blood being delivered to the left ventricle? Be sure that you
understand the mechanisms.
With the bronchoconstriction and decreased ventilation form the asthma attack, there will
be a decrease in the ventilation—perfusion ratio. A reduced VA/Q ratio is caused by
obstruction in ventilation but blood flow is unchanged. As PO2 will decrease and PCO2
increase. With complete obstruction , the O2 and CO2 of alveolar gas and end-capillary
blood must be the same as the mixed venous blood.

Inspired Air: O2 = 150 and CO2 = 0
(A) Normal VA/Q ratio. The mixed venous blood entering has PO2 of 40 and
PCO2 of 45. The alveolar PO2 of 100 is determined by balance between O2
addition via ventilation (PO2 inspired = 150) and its removal by blood flow.
(B) Reduced VA/Q ratio (Asthma/COPD). This is caused by obstruction
ventilation as blood flow is unchanged. When this happens alveolar PO2 will
decrease and PCO2 increase. The relative changes are hard to calculate with
partial obstruction. With complete obstruction, the O2 and CO2 of alveolar gas
and end-capillary blood must be the same as the mixed venous blood.
(C) Increased VA/Q ratio (PE): This is caused by obstruction of blood flow as
ventilation is unchanged. In this situation, PO2 will increase and PCO2 will
decrease, and the alveolar gas concentration will approach those levels of the
inspired air.
(2)
PBL CASE #3: FACULTY LEARNING ISSUES
With respect to asthma, describe its pathology, pathophysiology, and clinical
presentation.
PATHOLOGY
 Asthma is characterized by inflammation of the airway wall, with abnormal
accumulation of eosinophils, lymphocytes, mast cells, macrophages, dendritic
cells, and myofibroblasts.
 Inflammatory mediators and proteins secreted by these and other cells contribute
directly and indirectly to changes in airway structure and function.
 The structural changes are found in both the epithelium and the submucosa,
o abnormal deposition of collagen in the subepithelium
o hyperplasia and/or hypertrophy of goblet cells, submucosal gland cells,
smooth muscle cells, and blood vessel cells.
 Pathological changes seen in asthma
o airway surface becomes more fragile
o thickening of the epithelial reticular basement membrane
o inflammation of the airways
 Presence of an inflammatory infiltrate made of activated T-cell
and eosinophils.
PATHOPHYSIOLOGY
 Inflammation
o Airway inflammation is a key component of asthma and represents a
complex interaction of inflammatory cells and airway cells
o Proposed that individuals with appropriate susceptibility genes for
asthma, when placed in a specific early life environment, develop a
type of lymphocytic airway inflammation that results in asthma
o Thus, naive T cells may be encouraged to differentiate toward a Th2
subtype.
 Secretion of typical Th2 cytokines such as IL-4, IL-5, and
IL-13 in the airway promote eosinophilic and mast cell
inflammation and structural airway changes typical of the
asthma phenotype.
 The asthmatic airway inflammatory process, in which
eosinophils, mast cells, and lymphocytes are abundant
compared to normal subjects, is caused by the influence of
TH2 cells, producing mediators including IL-3, IL-4, IL-5, IL13, and granulocyte-macrophage colony-stimulating factor
(GM-CSF).
 Some of these mediators (IL-4) activate B lymphocytes to
produce IgE or the mediated cause the continuation of
eosinophilic airway inflammation (IL-3, IL-5, GM-CSF).
 Airway remodeling
o Structural changes in the airway including include goblet cell
metaplasia, deposition of collagens in the subepithelial space,
hyperplasia of airway smooth muscle, and proliferation of submucosal
glands.
 Results in thickening of the airway wall, and it involves both
cartilaginous (large) airways and membranous (small)
airways.
CLINCIAL
 Associated with variable airflow limitations that are at least partly reversible
either spontaneously or with treatment.
 Classic triad of symptoms
o Persistent wheeze – 35 %
o Chronic cough – 24 %
o Chronic dyspnea – 29%
 Physical Exam:
o Widespread, high-pitched wheezes (poor predictor of severity )
o Use of accessory muscles
o Pulses paradoxus (greater than 10mmHg and fall in systolic pressure
during inspiration)
(3)
3.
Immune mechanisms of asthma:
antigen presentation to naïve CD4+ T
cells by antigen-presenting cells
(dendritic cells) causes either a Th1 or
a Th2 response of CD4+ T cells
Regulators of Th1/Th2 differentiation
include IL-4, IL-10, and IL-12. Th2
cells secrete many different cytokines,
which may or may not utilize
inflammatory cells such as eosinophils,
mast cells, and B cells as effectors.
Airway remodeling in asthma is shown
by healthy airway wall on the left and
the asthmatic airway wall on the right.
In asthma there is goblet cell
hyperplasia/hypertrophy, subepithelial
fibrosis, increased vascularity, and
smooth muscle hypertrophy and
hyperplasia.
PBL CASE #3: FACULTY LEARNING ISSUES
4.
If you evaluate an asthma patient with a battery of pulmonary function tests
and give a rationale for your test selection and predict the results, what tests
would you use and why?
Expiratory Peak Flow
 Records airflow limitation by measuring the fastest rate of airflow during a
forced expiration.
 The readings over a period of 1-2 weeks may be used to accurately diagnose
asthma, estimate severity, and determine the response to treatment.
 Peak flow is also the best indicatory of response to therapy
Spirometry
 measures forced expiratory volume in one second (FEV1) and forced vital
capacity (FVC)
 The test is an accurate way to diagnose asthma and other airway diseases.
 With asthma and other obstructive lung diseases, the lungs fill up easily, but
cannot empty.
o TLC is normal
o FRC, RV are increased
o VC, FEV1, FEV1/VC% are decreased
 In comparison, with a restrictive lung disease, the lungs are less compliant than
normal
o TLC, IC, VC are decreased
o RV is normal
o FEV1/VC% is normal or increased
5.
Upon Mr. Vu’s initial evaluation, do you feel his problem was miss managed?
If so, why?
 Prior to this doctor visit, Mr. Vu was prescribed theophylline and an inhaled
steroid for his asthma therapy; he also had a PRN prescription for an inhaled Bagonist (albuterol). Based on his condition when he visited the clinic, it is
obvious that his care was mismanaged.
 From Mr. Vu’s history, no information was provided concerning previous peak
flow meter tests to determine the severity of asthma (mild intermittent, mild
persistent, moderate persistent, and severe).
o Based on his current symptoms, and his previous hospitalization for
asthma, Mr, Vu would be either in the moderate persisitant or severe
category.
 Based upon this evaluation, his therapy should have included a B-agonist
inhaler PRN + an inhaled steroid + a leukotriene inhibitor and/or long acting
beta agonist.
 In addition, Mr. Vu likely suffers from Samter’s Traid, which is characterized
by the clinical triad of asthma, nasal polyps and aspirin sensitivity (late).
o Treatment: Nasal steroids/inhaled steroids, and leukotriene antagonists
(which is the same as indicated for his asthma treatment). Surgery can
be done to remove polyps, although they typically recur.
 Mr. Vu also needs to be properly educated on how to use the inhalers.
 Theophylline was a controversial choice, as it is not indicated in first line asthma
treatment. Theophylline also has not been indicated to be greatly beneficial and
has toxicities and narrow therapeutic index. (diuretic effects, CNS stimulation)
(4)
PBL CASE #3: FACULTY LEARNING ISSUES
(5)
6. Compare and contrast recommended drug regimens for pure asthma vs COPD.
 COPD Treatment
o Smoking cessation
 Slows decline in FEV-1
o Asthma Therapy
 β-2 agonist bronchodialators
 Metered dose inhaler
o Anticholinergic Agents
 Inhaled ipratropium – first line therapy
 Additive effects of anticholinergics and beta-agonists
o Theophylline
 Use is controversial; watch for toxicity (very narrow
therapeutic index.)
o Corticosteroids
 Inhaled –may slow rate of decline of FEV-1
 Oral – up to 20% of patients may benefit
 Consider short term use for exacerbations
 Long term use only if all other meds are at maximal
therapy
o Supplemental Oxygen
 If O2 saturation < 88% on room air or < 85% with exertion
 Asthma Treatment
o Mild intermittent:

β -agonist inhaler PRN.
o Mild persistent
 β -agonist inhaler PRN. + inhaled steroid
o Moderate persistent
 β -agonist inhaler PRN. + inhaled steroid + leukotriene
inhibitor and/or long acting beta agonist
o Severe
 Multiple controller meds
 Consider oral steroids.
7.
Discuss patient education and involvement in his/her own treatment of chronic
lung disease. Discuss the issue of patient compliance with drug regimens and
monitoring PEFR.
 Low rates of patient compliance pose a major challenge to effective asthma
management.
 Non-compliance depends on many factors
o patient's own treatment goals
o social and economic factors
o administration route
o convenience of device
o side-effects
 Poor patient compliance may also be due to a discrepancy between the goals of
the clinician and those of the patient.
 Clinicians tend to focus on prevention of mortality and reduction of morbidity,
 PEFR rates takes an home by the patient are the most effective way at self
monitoring and control of asthma symptoms.
o Peak expiratory flow rates

“Red” – less than 50% of personal best
 Emergency situation for patient – may need oral
steroids
 “Yellow” – 50 to 80%
 Patient may need to take additional asthma meds may
to control worsening symptoms
 “Green” – Over 80%
 Asthma under control and patient just needs to track
what medications were taken that day
8.
Know the mechanism of
aspirin-induced
PBL CASE #3: FACULTY LEARNING ISSUES
(6)
hypersensitivity and the potential of cross-reactivity with any NSAID.





9.
The etiology of aspirin sensitivity is unknown but believed that the disorder is
caused by an disorder in the arachidonic acid cascade  increased
production of leukotrienes
o Mechanism 1: Blockade of COX shifts arachidonate utilization to the
lipoxygenase pathway. The end result is increased leukotriene
production and the symptoms of hypersensitivity.
 Upregulation of the Cys LTR1 is also seen.
o Mechanism 2: Inhibition of COX 1  decreased synthesis of PGE2.
 Removing this PGE2 eliminates its critical blocking effect on
5-lipoxygenase, allowing rapid synthesis of leukotrienes.
This increase in leukotrienes leads to delayed mast cell degranulation with a
subsequent release of histamine.
Aspirin is the dominant cause and other cyclooxygenase inhibitors can cause it
also.
People with aspirin sensitivity can have cross-reactivity to other non-steroidal
anti-inflammatory compounds such as ibuprofen and naproxen
o Even some documented cross-reactivity with acetaminophen.
But there is no cross-reactivity with selective cyclo-oxygenase 2 inhibitors.
Describe the proper use of an inhaler. Is nebulizer as a treatment more
effective than an inhaler?
MDI W/O SPACER (Albuterol/Combivent)
 Remove the cap from the mouthpiece and shake the inhaler
 Breathe out to the end of a normal breath, position the mouthpiece end of the
inhaler about 2-3 finger widths from mouth.
 Close your lips around the mouthpiece and start to breathe in slowly
 Push down once on the container; this will spray medication into mouth.
 Continue breathing in slowly until lungs are full
 Once a full breath is reached, hold breath for 10 seconds or as long as possible,
then breathe out normally
 If a second puff needed, wait one minute and repeat steps.
MDI W/ SPACER (Albuterol/Combivent)
 Remove the cap of the inhaler and shake well
 Insert the inhaler in the inhaler adaptor at the back of the spacing chamber
 Exhale as much as possible until lungs feel empty.
 Seal lips around the spacing mouthpiece
 Press down once on the inhaler's container, which will spray medication into the
chamber
 Breathe in slowly and deeply
 Once breathed in fully, hold breath for 10 seconds or as long as possible, then
exhale normally
USE OF DISK INHALER (Advair)
 Seal lips around the mouthpiece.
 Inhale rapidly and deeply. Continue to take a full, deep breath.
 Hold breath for up to ten seconds. This allows the medication time to deposit in
the airways.
 Resume normal breathing
NEBULIZER VS. MULTIPLE DOSE INHALER (MDI)
 Research comparing efficacy of nebulizers and MDI has shown no difference
between the two treatment groups with regard to hospital admission rates.
 However, the use of the MDI with spacer provided greater improvement in
peak-flow rates than use of the nebulizer.
 MDI users had a lower total albuterol dose and showed greater improvement
in arterial blood gases.
 Asthma relapse rates were significantly lower for the MDI users than for
nebulizer users treated by nebulizer.
Mechanism of Aspirin Sensitivity:
blockage of the COX pathway causes a
shift to the LOX pathway leading to an
increase production of leukotrienes 
mast cell degranulation  histamine
release  bronchoconstriction
PBL CASE #3: FACULTY LEARNING ISSUES
(7)
Class
1st generation antihistamine
Mechanism
Block H1, muscarinic, adrenergic, and
serotonin receptors
Distribution
Oral, widely
distributed (CNS)
Elimination
Transformed in liver, excreted
in urine
Fexofenadine
2nd generation antihistamine
Loratidine
2nd generation antihistamine
Theophylline
Methylxanthine; bronchodilator
Cromolyn sodium
Anti-asthma; mast cell
destablizer
Oral, does NOT enter
CNS
Oral, does NOT enter
CNS
Oral, wide
availability
Poorly absorbed,
inhalation only
Transformed in liver, excreted
in urine
Transformed in liver, excreted
in urine
Metabolized by liver, excreted
by kidney
N/A
nedocromil
Anti-asthma; mast cell
destablizer
Adrenergic agonist;
bronchodilator, alpha-1, β1, β2
Block H1, muscarinic, adrenergic, and
serotonin receptors
Block H1, muscarinic, adrenergic, and
seratonin receptors
Antagonists of adenosine receptors, ↓
histamine release, bronchodilation
↓ histamine release, reduction in
bronchospasms (no relaxation of
smooth muscle), value when taken
prophylactically
inhibits the release of histamine from
mast cells
Relaxes the bronchioles via β2
activation, used in anaphylaxis
Poorly absorbed,
inhalation only
Inhalation/injection
Not metabolized, eliminated by
kidney
Metabolized rapidly in liver my
COMT/MOA, kidney
elimination
Releases norepinephrine and causes
bronchiole relaxation by direct effect
Bronchiole relaxation, inhibits mast
cell degranulation
Oral administration
Diphenhydramine
Tripelennamine
Chlorpheniramine
Hydroxyzine
Promethazine
Epinephrine
Ephedrine
Sympathomimetic, adrenergic
Metaproterenol
β2 agonist, bronchodilator
Metabolized in GI tract
Terbutaline
Poor oral availability,
Inhalation
Inhalation/IV
Albuterol/Salbutamol
Inhalation
Kidney elimination
Inhalation
Hepatic metabolism/fecal
elimination
P450 metabolism (watch for
hepatic toxicity)
Hepatic metabolism, fecal
elimination
Hepatic metabolism, fecal
elimination
Salmeterol
Long acting
Zilueton
Leukotriene Inhibitor
Phenylephrine
α1 agonist, decongestant
Inhibits 5-lipoxygenase and prevents
formation of LTB4 (chronic asthma)
Leukotriene receptor antagonist (LTD4
receptor)
Leukotriene receptor antagonist (LTD4
receptor)
Constriction of vasculature
Pseudoephedrine
Sympathomimetic, adrenergic
agonist
Glucocorticoid; anti-
Releases norepinephrine and causes
bronchiole relaxation
Inhibits inflammatory cells and release
Zafirlukast
Montelukast
Betamethasone
Oral availability
Oral administration
Oral availability
Oral availability
Kidney elimination
Oral availability
Inhalation/nasal
Metabolized in liver, excreted
Side Effects
Low incidence of GI side effect, ↑
sedation, used for motion sickness
GI side effects common, few CNS
effect, fewer anticholinergic effects
No sedative effects, good for day
time use
Sedation (↑), longer lasting,
potentially teratogenic
Used as anti-psychotic/anti-emetic,
↑ anticholinergic effects, used for
motion sickness (antichol effect)
Minimal anticholinergic effect, NO
sedation
Minimal anticholinergic effect, NO
sedation
Insomnia, nervousness,
arrhythmias, GI bleeding, vomiting
Sore throat, cough, dry mouth,
nausea, headache
Cough, bad taste in mouth,
nausea/vomiting, headache
Arrhythmia, tachycardia, sweating,
nausea/vomiting
Hypertenstion, palpitations,
nausea/vomiting
Muscle tremors, nervousness,
palpitations
Muscle tremors, nervousness,
palpitations
Muscle tremors, nervousness,
palpitations
Long acting, tachycardia, headache,
tremor
P450 drug interactions; diarrhea,
indigestion, headache, vomitting
Inhibits P450, many drug
interactions
Inhibits P450, many drug
interactions
Hypertension
Hypertension, tachycardia,
insomnia, anxiety
Immunosuppresion (long term
PBL CASE #3: FACULTY LEARNING ISSUES
Dexamethasone
(8)
inflammatory steroid
of inflammatory mediators.
Class
Glucocorticoid; antiinflammatory steroid
Mechanism
Inhibits inflammatory cells and inhibits
release of inflammatory mediators.
(decrease arachidonic acid release, dec
degranulation of mast cells)..inhibits
phospholipase A2
spray, can have some
systemic distribution
Distribution
Orally available.
Careful with abrupt
cessation b/c person
shut off synthesizing
own steroids
Methylprednisolone
Orally available
Prednisone
Orally available
Triamcinolone
Orally available,
inhalation
Beclamethasone
Inhalation/nasal
spray, can have some
systemic distribution
Flunisolide
Inhalation/nasal
spray, can have some
systemic distribution
Inhalation/nasal
spray, can have some
systemic distribution
Bedesonide
Fluticasone
Inhalation/nasal
spray, can have some
systemic distribution
by kidney
Elimination
Metabolized in liver, excreted
by kidney
usages, headache, most anti-inflam.
along with dexamethasone
Side Effects
Immunosuppresion (long term),
headache, oral candidiasis (thrush),
dysphonia, hoarseness, reflex cough
and bronchospasm, (systemic:
weight gain, fluid retention, elev
blood sugars, osteoporosis, growth
suppression, cataracts…same with
all systemic glucocort..for severe
asthma)..bolded are main ones for
glucocort.
Immunosuppresion (long term),
headache, oral candidiasis (thrush),
dysphonia, reflex cough and
bronchospasm
Immunosuppresion (long term),
headache, oral candidiasis (thrush),
dysphonia, reflex cough and
bronchospasm
Immunosuppresion (long term),
headache, oral candidiasis (thrush),
dysphonia, reflex cough and
bronchospasm
Immunosuppresion (long term),
headache, oral candidiasis (thrush),
dysphonia, reflex cough and
bronchospasm, fewer side effects
Most potent of steroids, fewer side
effects, nasal irritation
Immunosuppresion (long term),
headache, oral candidiasis (thrush),
dysphonia, reflex cough and
bronchospasm
Immunosuppresion (long term),
headache, oral candidiasis (thrush),
dysphonia, reflex cough and
bronchospasm, nasal irritation