cardio/respiratory: asthma (lecs 1-4)

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