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asthma pathophysiology
obstructive and inflammatory lung disease
airway hyperresponsiveness/bronchial hyperactivity is an exaggerated response to numerous exogenous and endogenous stimuli
exercise/strong odors/bugs/pollen/etc
inflammatory disease of the airway
stimuli can cause mast cell activation and infiltration of inflammatory markers → leads to mucus secretion and bronchial constriction
the prescience of airway edema and mucus secretion also contributes to airway obstruction
inflammatory disease
inflammatory cells and mediators cause clinical characteristics and pathophysiological changes leading to expiratory airflow limitation
airway narrowing due to smooth muscle contraction and airway plugging by mucus hypersecretion also causes many of the symptoms that pts with asthma could experience (troubling breathing, wheezing, etc)
bronchial hyperresponsiveness (BHR) is possible and heightened in response to a stimulus such as an allergen
asthma eval. and diagnosis
“collect” in the patient-care process
clinical features
signs and symptoms
pulmonary function testing
other tests
CBC with differential
exhaled nitric oxide
skin testing
asthma clinical feautures
can develop at any age
most common in children
symptoms often brought on by triggers
remission is often experienced around puberty
potential for recurrence in later years
adolescence/young adults with asthma symptoms most often have previous history of asthma as a child and went into remission, but symptoms returned
asthma signs and symptoms
dyspnea (trouble breathing)
cough
chest tightness
wheezing
often occurs at night
FEV1/FVC ratio <0.7 in adults or <0.9 in children
pulmonary function testing (for asthma dx)
spirometry
bronchodilator response
peak flow meters
clinical presentation of asthma
pt often comes in with persistent cough (especially at night!), SOB, chest tightness
may have a family hx of asthma or allergies
may have a social hx of allergen exposure (dust/smoke/etc)
in their physical exam, they may have
a change in respiratory rate or oxygen saturation with acute symptoms
a change in posture with acute sx (tripod position)
wheezing may be heard during lung exam
can help determine severity
there may be few sx when in remission or mild cases
spirometry in asthma
FEV1/FVC ratio detects airflow obstruction
so, for these pts, they would have a reduced ratio (<0.7 or <0.9 in children)
(normal is >0.7 in adults, >0.9 in children)
bronchodilator response
an increase in FEV1 or FVC by >12% of mean predicted value
mean predicted value = [(post-bronchodilator value - pre-bronchodilator value) *100] / predicted value
pts would do a spirometry test, then receive 2-4 metered dose inhalations of a short-acting beta agonist, and repeat the spirometry test
basically, did their spirometry improve (at least by 12%) after the use of a bronchodilator?
this would demonstrate that airflow limitation is reversible following acute treatment with a beta-agonist
airflow limitation reversibility would suggest that the disease state could in fact be asthma
if there is no reversibility, then it suggests an alternate dx should be considered
peak flow test
a small portable device that can measure the maximally forced expiration, aka the peak expiratory flow (PEF)
can be used if spirometry is not available, and can be also be used at home to assess asthma control
can develop an Asthma Action Plan at home
pt would complete the testing 2-4x daily for 2 weeks when the asthma is well controlled, and determine their personal best, and then utilize their personal best to further assess control
assessing control with a peak flow meter
can use a pt’s personal best, or look at a normal peak flow rate determined on a pt’s age, sex, height, and race:
between 400-700 L/min in adults
150-450 L/min in children
to track asthma control, pts can determine which “zone” they’re in:
green zone: 80-100% of usual or normal peak flow
well controlled, no changes need to be adjusted
yellow zone: 50-80% of normal peak flow
exposure to an allergen, control is starting to go down
red zone: <50% of normal peak flow
danger zone, escalate tx or get them seen asap
exhaled nitric oxide test
eosinophilic airway inflammation associated with asthma causes up-regulation (increased amount) of nitric oxide synthase which becomes elevated in exhaled breath
remember, asthma is highly associated with high levels of eosinophils
a concentration of nitric oxide (fractional exhaled nitric oxide (FENO)) ≥ 40-50 parts per billion can help “rule in” asthma
other dx can lead to increased FENO, so these would need to be ruled out (allergic rhinitis, eosinophilic bronchitis, etc)
this test is not just specific for asthma, need to use other diagnostic measures as well
complete blood count (CBC) with differential
assess for eosinophilia or anemia
these are associated with trouble breathing if RBC count is low
elevated eosinophils (>300 microL) may be candidates for monoclonal Ab therapy
indicative of more severe asthma
(some) factors impacting asthma control
smoking
physical activity/exercise
weight or diet
medications (eg. beta blockers)
weather
stress
allergens
respiratory infections
adherence to current regimen
inhaler technique
social determinants of health for asthma
housing → mold or rodent exposure
neighborhoods with high pollution
cost and coverage of medications
goals for asthma management
achieve good control of sx
maintain normal activity levels
minimize use of rescue inhalers (SABA)
minimize risk of exacerbations
minimize medication-related side effects
minimize risk of hospitalization/death
medications for asthma (classes)
anti-inflammatory drugs
bronchodilators
leukotriene antagonists
anti-inflammatory drugs
inhaled corticosteroids (ICS)
also systemic corticosteroids
mast cell stabilizers
much less efficacy, and thus much less commonly used
biologics
bronchodilators
beta agonists
short-acting (SABA) and long-acting (LABA)
muscarinic antagonists/anti-muscarinics
short-acting (SAMA) and long-acting (LAMA)
methylxanthine
leukotriene antagonists
leukotriene receptor antagonists
5’ lipoxygenase inhibitors
delivery for asthma medications
metered dose inhalers
can add a spacer or holding chamber to improve coordination
dry powder inhalers
soft mist (Respimat) devices
nebulized solutions
reliever (rescue) treatment
asthma inhaler taken as needed for quick relief of sx or prior to exercise
these are SABAs (such as albuterol) that work quickly as needed for acute exacerbations or immediate symptom alleviation
anti-inflammatory reliever (AIR)
a subcategory of rescue treatments which is a reliever that contains a low dose inhaled corticosteroid (ICS) and a rapid-acting bronchodilator
ICS-SABA or ICS-formoterol
the idea behind this is to add on an ICS to supplement the use of the beta agonist or the bronchodilator in order to help it work better and reduce the resistance we sometimes see when using a beta agonist by itself
the ICS is working on the underlying cause of the sx of asthma
maintenance (controller) treatment
for pts with more persistent or moderate to severe asthma, in which asthma tx is prescribed for scheduled everyday use to control symptoms
the goal is to decrease the need to use frequent rescue treatment
ICS or ICS/LABA or ICS/LABA/LAMA
monotherapy or combination therapy with ICSs
single-inhaler maintenance and reliever therapy (SMART/MART)
reflects the treatment regimen in which the pt uses an ICS-formoterol inhaler everyday (maintenance) and also for as needed relief of asthma symptoms (rescue)
basically, pt has one inhaler, ICS-formoterol, that they’re using in multiple different ways
has reduced exacerbation rates and corticosteroid use, but has inconistent effects on asthma control and quanity of life
usually 2x daily
short-acting beta agonists (SABA)
rescue inhalers
first-line tx for management of acute asthma exacerbation
used as needed for symptoms such as SOB or wheezing or prior to exercise or allergen exposure
water-soluble
MOA of SABAs and LABAs
relaxes bronchial smooth muscle by action on beta-2 receptors within airway
has no effect on inflammation!!
doesn’t work on the underlying cause of asthma (inflammation), but works on symptom management to allow for more air to pass through the airway (bronchodilation)
SABA drugs
albuterol inhaler (90 mcg/dose)
albuterol nebulizer solution
levalbuterol (45 mcg/dose)
albuterol sulfate
brand names
Proair HFA
Proair RespiClick
Proair Digihaler
Proventil HFA
Ventolin HFA
levalbuterol HCl
brand name
Xopenex HFA
dosing for SABA (intermittent)
1-2 puffs q4-6h prn
dosing for SABA (exercise-induced)
2 puffs 5-20 mins prior to exercise
dosing for SABA (acute exacerbation)
2-10 inhalations q20 mins for 3 doses
then taper as tolerated
efficacy of SABAs
quick onset (1-2 mins)
short-acting (4-8 hours)
tolerance can develop over time with high usage
can lead to down-regulation (decreased number) of beta-2 receptors and a decreased binding affinity for these receptors (desensitization) due to overuse
there is an increased mortality if using >1 canister per month
~120 doses per canister
if pt is using medication so much, might want to add a maintenance inhaler to reduce usage
side effects of SABAs and LABAs
relatively localized, however there is some risk of systemic absorption → heart effects due to beta receptors located in other parts of the body
increased HR
possibly less with levalbuterol
palpitations
tremors
decreased K+
drug-drug interactions with SABAs and LABAs
usually low risk
drugs that cause increased HR (sympathetomimetics)
drugs that decrease K+ (diuretics)
beta-blockers (non-selective BBs such as propanol)
directly antagonizes what this medication is trying to do
monitoring for SABAs and LABAs
frequent of use, tolerance
inhaler technique
adherence to regimen
would be evidenced by their (continuing) SOB, wheezing, etc, or side effects
primatene mist
epinephrine 0.125 mg spray
acts as a beta agonist
OTC approved agent for mild intermittent asthma sx
clinical practice guidelines do not recommend use for routine management of asthma due to potential for excessive cardiac stimulation
since OTC, usually no one to monitor how frequent they are using
long-acting beta agonists (LABA)
lipid-soluble
readily move into the outer phospholipid layer of the cell membrane
more beta-2 selective than albuterol and more bronchial-selective since they remain in the lung tissue due to lipophilicity, which allows for a longer duration of time
LABA drugs
formoterol, vilanterol, or salmeterol + an ICS (combination therapies)
LABAs should not be used alone
efficacy of LABAs
controller (maintenance) therapy
adding drug to ICS is more effective than increasing ICS alone
must be used in combination with ICS for asthma
BBW for monotherapy: when used by themselves, there is an increased risk of asthma related death
formeterol
quick-acting AND long-acting (for 12 hrs)
vilanterol
ultra-long acting (for 24 hrs)
inhaled corticosteroids (ICS)
preferred long-term controller therapy for persistent asthma
any pt with persistent asthma should be on this for asthma management
works on the underlying pathophysiology of asthma (inflammation!)
reduces BHR, improves lung function, reduces severe exacerbations leading to ED/hopsitalizations
only tx documented to reduce the risk of death from asthma
MOA of ICS
combines with a glucocorticoid receptor in cytoplasm, which then enters the nucleus where it acts as a transcription factor leading to gene alteration
altered mRNA production increases anti-inflammatory mediators and suppresses pro-inflammatory cytokines
response is delayed because of this
improvement in 1-2 weeks with maximum improvement in 4-8 weeks
ICS drugs
fluticasone propionate/furoate
mometasone
budesonide
beclomethasone
efficacy of ICS
backbone of asthma therapy due to anti-inflammatory effects
high topical potency in the lungs with low systemic activity
improvement in 1-2 weeks with maximum improvement in 4-8 weeks
side effects of ICS
thrush/yeast infections within the mouth and throat
due to immunosuppression
counsel the pt to rinse and spit!
dysphonia (trouble talking)
throat irritation
growth delay in first 1-2 yrs in pediatric pts
at higher doses (less likely):
osteoporosis
adrenal axis suppression
immunosuppression
HTN
hyperglycemia
drug-drug interactions with ICS
3A4 inhibitors
cigatette smoke can reduce the efficacy
beclomethasone
brand name
Qvar Redihaler (40 or 80 mcg)
BID
budesonide
brand names
Pulmicort Respule (0.25 mg)
1x daily
Pulmicort Flexhaler (90 or 180 mcg)
BID
ciclesonide
brand name
Alvesco
fluticasone propionate
brand names
Flovent Diskus (50,100,250 mcg)
BID
Flovent HFA (44,110,220 mcg)
BID
fluticasone furoate
brand name
Arnuity Ellipta (50,100,200 mcg)
1x daily
mometasone
brand names
Asmanex HFA (50,100,200 mcg)
BID
Asmanex Twisthaler (110 or 220 mcg)
1x daily or BID
SMART therapy (ages 4-11)
budesonide/formeterol
maximum formeterol dose is 8 inhalations per day (36 mcg)
2 puffs BID for maintenance
4 puffs prn left for rescue
however if pt is using that much rescue puffs, it would suggest that their asthma is not well controlled, and may need esclate therapy (increasing dose, or other meds)
SMART therapy (ages 12+)
budesonide/formeterol
maximum formeterol dose is 12 inhalations per day (54 mcg)
2 puffs BID for maintenance
8 puffs prn for rescue
however if pt is using that much rescue puffs, it would suggest that their asthma is not well controlled, and may need esclate therapy (increasing dose, or other meds)
budesonide/formoterol
brand name
Symbicort HFA (80/4.5 or 160/4.5 mcg)
2 puffs BID for maintenance
often used for SMART therapy
mometasone/formeterol
brand name
Dulera (50/5, 100/5, 200/5 mcg)
much less studied than Symbicort
albuterol/budesonide 90/80mcg
brand name
Airsupra Aerosphere
first SABA/ICS combination to be used as a reliver in pts 18+
an example of an anti-inflammatory reliever (AIR) therapeutic combination
take 2 puffs po prn
fluticasone/salmeterol
brand names
Advair HFA
45/21, 115/21, 230/21 mcg
Advair Diskus
100/50, 250/50, 500/50 mcg
Airduo
55/14, 113/14, 232/14 mcg
Wixela Inhub
100/50, 250/50, 500/50 mcg
all brands taken BID
fluticasone/vilanterol
brand name
Breo Ellipta (100/25 or 200/25 mcg)
1x daily
MOA of muscarinic antagonists
blocks the action of acetylcholine in bronchial smooth muscle which results in bronchodilation
short-acting (SAMAs) or long-acting (LAMAs)
SAMAs are not preferred for asthma tx
since they have different MOAs, they can be used in combination with SABAs or LABAs
ipratropium
brand name
Atrovent HFA
SAMA
tiotropium
brand name
Spiriva Respiamt
LAMA
ICS/LABA/LAMA therapy
Trelegy Ellipta
MOA of leukotriene modifiers
blocks the action of inflammatory mediators released by immune cells
basically blocks the inflammatory cascade seen in asthma pts
leukotriene modifier drugs
montelukast (Singulair)
zafirlukast (Accolate)
Zileuton (Zyflo)
all come in the form of pills! (not inhalers)
dosing for montelukast (ages ≥ 15)
10 mg po once daily
dosing for montelukast (ages 6-14)
5 mg po once daily
dosing for montelukast (ages 12mo-5 yrs)
4 mg po once daily
dosing for zafirlukast (ages ≥ 12)
20 mg po BID
dosing for zafirlukast (ages 5-11)
10 mg po BID
dosing for zileuton (ages ≥ 12)
IR: 600 mg po QID
ER: 1200 mg po BID
efficacy of leukotriene modifiers
most commonly used for allergic-type asthma or (co-morbid) allergic rhinitis because it works well to suppress those immune cells that are brought forth due to allergic reactions
oral pill, so much easier for pts who have difficulty taking an inhaler (especially pediatrics)
and doesnt affect growth like ICS might
once daily doses are available
alternative therapy to LABAs when added to ICS but less effective
side effects of leukotriene modifiers
hepatic dysfunction (mostly seen with the Z-drugs)
BBW: neuropsychological effects
agitation, aggression, depression, memory disturbances, suicidal thoughts/behaviors, attention deficit, sleep disturbances, etc
contraindications for Zileuton
pts with active liver disease or liver function tests (LFTs) ≥ 3x the upper limit of normal
thus, less desirable than montelukast due to limited studies and the need to monitor liver function
take with food
drug-drug interactions for leukotriene modifiers
minimal interactions
however, may want to take caution against drugs that also affect neuro/psych or mood
monitoring/education for leukotriene modifiers
changes in behaviors, mood, or sleeping
liver function tests for the Z-drugs
look out for changes in disease progression
for pediatrics, some dosage forms may come as chewables/granules/liquid
can be mixed with 5mL of juice, breast milk or applesauce
MOA of mast cell stabilizers
prevents the subsequent release of inflammatory mediators, including histamine and leukotrienes, which cause allergic symptoms and bronchoconstriction
mast cell stabilizer drugs
cromolyn
comes as a nebulizer solution
side effects of mast cell stabilizers
nausea
cough
wheezing
nasal congestion
MOA of biologics (for asthma tx)
targets the IgE or interleukin pathway to reduce inflammation
highlights of biologics therapy
very expensive, not very accessible
look at the predictors of response and comorbidities
may do IgE test or look at levels of eosinophils to determine if the pt has high levels of inflammation to see if this medication class would make sense
in general, the criteria to be on this drug includes a pre-bronchodilator FEV1 between 40-80% of predicted and one or more exacerbations in the past year despite moderate-to-high doses of ICS
basically, the pt’s asthma is not well-controlled despite valid medical intervention
once pt starts treatment, a trial of 4 months is recommended, but if unclear can continue for 6-12 months
but if the pt is not noticing benefit, medication would be d/ced or changed
biologic place in therapy
usage is reserved for pts with moderate-to-severe persistent asthma with poor symptom control despite treatment with high doses of ICS-LABA
indicated for pts with relevant biomarkes or need for maintenance systemic corticosteroid
look out for injection site reaction
ADEs: respiratory tract infections, may worsen asthma
omalizumab
brand name
Xolair
targets IgE pathway
BBW for anaphylaxis
mepolizumab
brand name
Nucala
targets IL-5 pathway
reslizumab
brand name
Cinquair
targets IL-5 pathway
BBW for anaphylaxis
for pts 18+
benralizumab
brand name
Fasenra
targets IL-5Ra pathway
dupilumab
brand name
Dupixent
targets IL-4Ra pathway
tezepelumab
brand name
Tezpire
targets TSLP pathway
methylxanthine drugs
theophylline
methylxanthines
moderately potent bronchodilator with mild anti-inflammatory properties
old medication, no longer preferred
risk of severe toxicity (seizures, death)
requires regular blood monitoring
reduced efficacy vs ICS, LABAs, and biologics
many DDIs
thus, last-line treatment
indication for systemic corticosteroids
acute severe asthma exacerbation that is not responding to SABA administration
short courses are recommended and do not require taper
5-7 days in adults
3-5 days in children
systemic corticosteroid drugs
prednisone
prednisolone
methylprednisolone
side effects of systemic corticosteroids
growth suppression
immunosuppression
adrenal insufficiency/Cushing’s disease
weight gain
HTN
hyperglycemia
GI bleed
cataracts
insomnia
psychological disturbances
drug-drug interactions for systemic corticosteroids
immunosuppressants
drugs that have similar ADEs
3A4 inhibitors can increase levels in the body leading to more pronounced or higher risk of ADEs
what severity of asthma is determined by per the NAEPP
lung function (spirometry)
symptoms
nighttime awakenings
rescue SABA use
interference with normal activity
frequency of exacerbations requiring systemic corticosteroids
general approach to management of chronic asthma
stepped approach based on age and whether pt is newly diagnosed (treatment naive) or requires treatment adjustments
initial step for newly diagnosed pts is based on greatest level(s) of impairment
all pts with mild, moderate, or severe should be initiated on ICS as maintenance therapy
all pts should have quick relief medication (rescue) to be used as needed for acute symptoms
ensure pts undersand how to use the inhaler and the differences between controller and rescue inhalers
validated questionnaires for asthma management
asthma therapy assesment questionnaire (ATAQ)
symptoms in the past 4 weeks; 4 questions
asthma control questionnaire (ACQ)
7 items, 1 week recall (for items on symptoms and rescue inhaler use)
asthma control test (ACT)
symptoms in the past 4 weeks