2.1 - Asthma

Asthma

• chronic inflammatory disorder of the airways

• involves complex interactions between many cells and inflammatory mediators that result in inflammation, obstruction, increased airway responsiveness, and episodic asthma symptoms

• mild intermittent asthma

• mild

• moderate

• severe persistent asthma

Asthma severity classifications (4)

impairment

frequency and intensity of symptoms and functional limitations the patient is currently experiencing or has recently experienced

risk

likelihood of asthma exacerbations, progressive decline in lung function or adverse effects from medications

• aspirin

• NSAIDs

• antiadrenergic & cholinergic drugs

• preservatives (tartazines, sulfites, benzalkonium chloride)

• excipients derived from legumes (soybeans)

Problematic drugs include:

Inflammatory cells

• secrete mediators and influence the airways directly or via neural mechanisms

• responsible for altered mucociliary function, epithelial disruption ranging from minor ciliary loss to severely denuded epithelium, increased airway permeability and reduced clearance of inflammatory mediators.

Airway obstruction

responsible for many of the clinical manifestations of asthma

• Airway obstruction

• ventilation/ perfusion (V/Q)

• hypoxemia

______ reduces ventilation to some lung regions, which causes a ______ imbalance that leads to ______

Hyperresponsiveness

exaggerated response to certain stimuli, is an important feature of asthma and appears to correlate with clinical severity and medication requirements

• Increased levels of inflammatory mediators

• infiltration by inflammatory cells

2 primary mechanisms responsible for airway hyperresponsiveness

Airway inflammation

crucial to development of asthma and contributes to airway hyperresponsiveness, airflow obstruction, respiratory symptoms, and disease chronicity

Acute inflammation

inflammation that is associated with early recruitment of cells to the airway

Subacute inflammation

inflammation that is associated with recruited and resident cell activation, resulting in more persistent inflammation

Chronic inflammation

inflammation that is associated with persistent cell damage and ongoing repair, resulting in airway abnormalities that may become permanent

• increased cholinergic sensitivity

• muscarinic receptor

In altered autonomic neural control, elevated parasympathetic tone and reflex bronchoconstriction may occur as a result of ______ or a change in ______ function

• smooth muscle hypertrophy

• nerve endings

In altered autonomic neural control, increased smooth muscle responsiveness may be the result of ______. Exposure of the _____, caused by inflammation, may also contribute

Airway remodeling

can result from persistent inflammation to chronic asthma

Hypertrophy

another form of tissue remodeling in asthma

• immunoglobulin E (IgE)

• mast

In an allergic asthma patient, aft er exposure to an allergic trigger, the antigen binds to ______, which is attached to activated ____ cells

early asthmatic response

• begins within 30 mins of trigger exposure and resolves within 2 hrs

• results in constriction of the airway smooth muscles, bronchospasm, and subsequently asthma symptoms

short-acting B-agonists

early asthmatic response can be blocked by _____

late asthmatic response

• involves a second decline in lung function, 4 to 8 hrs after the initial trigger exposure

• an inflammatory response, characterized by persistent airflow obstruction, airway inflammation, and bronchial hyperresponsiveness

• inhaled corticosteroids

• leukotriene modifiers

late asthmatic response can be blocked by _____

I Mild

This stage of asthma involves:

• Breathlessness while walking, speaks in sentences, moderate wheezing

• FEV₁ or FVC: >70% normal

• arterial pH: normal or ↑

• PaO₂: normal or ↓

• PaCO₂: normal or ↓

II Moderate

This stage of asthma involves:

• Dyspnea while at rest, in phrases, loud wheezing throughout expiration

• FEV₁ or FVC: 40-69% normal

• arterial pH: ↑

• PaO₂: >60 mmHg

• PaCO₂: <42 mmHg

III Severe

This stage of asthma involves:

• Breathlessness while at rest, speaks in words loud wheezing, coughing difficulty speaking, accessory chest muscle use, and chest hyperinflation

• FEV₁ or FVC: <40% normal

• arterial pH: normal or ↓

• PaO₂: <60 mmHg

• PaCO₂: >42 mmHg

IV Respiratory failure

This stage of asthma involves:

• Severe respiratory distress, confusion lethargy, cyanosis disappearance of breath sounds, and pulsus paradoxus, >12 mm Hg

• FEV₁ or FVC: <25% normal

• arterial pH: ↓↓

• PaO₂: ↓

• PaCO₂: ↑↑

• chronic hyperinflation

• barrel chest

• decreased diaphragmatic excursion

Patients with chronic, poorly controlled, severe asthma may have evidence of _______, including ______ and ______

Acute exacerbations

• sudden or gradual onset

• nocturnal or early morning

Pulmonary function tests

tests used to determine the degree of airway obstruction and may be normal between exacerbations

spirometry

____ in all asthma patients > 5 years old is recommended to determine that airway obstruction is at least partially reversible. It is used to generate the FEV1 and FVC.

• spirometry

• peak flow meter testing

Breathing tests include (2)

• forced expiratory volume in 1 second (FEV1)

• forced vital capacity (FVC)

both decrease during an acute exacerbation

• Residual volume (RV)

• total lung capacity (TLC)

may increase in asthma because of air trapping and subsequent lung hyperinflation (2)

• Peak expiratory flow rate (PEFR)

• peak flow meter

_____ obtained through the patient forcefully breathing out into a _____, correlates well with FEV1.

PEFR measurement

can be used to monitor control of asthma

• severe exacerbations

• poor perceivers of asthma symptoms

• moderate-tosevere disease

PEFR monitoring at home is recommended for patients who have had (3)

early morning

PEFR is best measured in _____, before medication administration

Provocation testing with histamine or methacholine challenge

may be performed to assess hyperresponsiveness and to rule out asthma in a patient who has had normal pulmonary function test results but in whom asthma is still suspected

• WBC

• WBC demargination

• corticosteroids

blood analysis shows a slightly increased _____ count during an acute exacerbation. Leukocytosis may be present because of _____ that occurs when patients receive systemic ______

Pulse oximetry

noninvasive means of assessing the degree of hypoxemia during an acute exacerbation.

• arterial blood (Sao2)

• pulse

a pulse oximeter measures oxygen saturation in ______ and _____

Arterial blood gas measurements

may be required to help gauge the severity of the asthma exacerbation

• hyperventilation

• decrease

• increases

In the early stages of an asthma exacerbation, ______results in a _____ in the partial pressure of arterial carbon dioxide (Paco2). If the exacerbation progresses and the airways remain narrowed, respiratory muscles may fatigue and the Paco2 level ______

Respiratory acidosis

• poor prognostic sign

• develops if hypoxemia worsens and the patient’s respiratory rate is not maintained owing to respiratory fatigue. This results in a rising Paco2 level.

electrocardiogram (ECG)

• may show sinus tachycardia

• useful in an older patient

chest radiograph

• may be normal or could detect accompanying pneumothorax, atelectasis, or pneumonia

• may also be needed to exclude other causes of the patient’s symptoms

Inhaled steroids

first-line anti-inflammatory agents in asthma

• formoterol/budesonide

• fluticasone/ salmeterol

• mometasone/formoterol

• Combination products for asthma

• These products are indicated for moderate or severe persistent asthma

• increasing

• long-acting B₂-agonist

The 2007 NHLBI asthma guidelines give equal weight to _____ the dose of the inhaled steroid compared to adding a ______ to the inhaled steroid in uncontrolled chronic asthma

Inhaled B-agonists (albuterol & levalbuterol)

used as needed for acute symptoms for all levels of severity

long-term

Daily or increasing use of a short-acting inhaled B₂-agonist suggests the need for additional ____ controller therapy

• inhaled B-agonist

• montelukast

• nedocromil

Pretreatment with either an _____, ______, or _____ may be used before exercise or allergen exposure.

Short-acting B-agonists (albuterol etc.)

drug of choice for EIB

15

In EIB, Short-acting B-agonists should be administered ___ mins before exercise

• Long-acting B-agonists—salmeterol and formoterol

• 30-60

• 12

• 15

______ should be administered ____ to ____ mins before exercise. When salmeterol is used chronically for EIB, some patients may lose protection toward the end of the ___-hr dosing interval. Because of its rapid onset, formoterol may be dosed ____ mins before exercise.

Nedocromil

• may be used to prevent EIB and exacerbations related to exposure to other asthma triggers

• administered no more than 1 hr before exercise or exposure

Leukotriene modifiers

help with EIB when given daily but should not be used on an “as-needed” basis just before exercise

obstructive lung disease

GERD is frequent in persons with ______

proton pump inhibitors (PPIs) (pantapraozole)

Management of GERD with _____, can improve asthma symptoms

Short-acting B-agonists

best reserved for worsening symptoms, treatment of acute exacerbations, and prophylaxis for EIB

• Maintenance treatment of moderate and severe persistent asthma + inhaled corticosteroids (nocturnal symps.)

• Prophylaxis of EIB

• px w/ asthma & concurrent COPD

Indications for long-acting B-agonists (3)

Long-acting B₂-agonists

should not be used as sole therapy for an acute asthma exacerbation in lieu of short-acting agents

long-acting B-agonist

Research indicates that rather than increasing the dose of the inhaled corticosteroid in uncontrolled chronic asthma, adding a ______ results in a greater improvement

B-Agonists

sympathomimetic agents that relieve bronchoconstriction during acute asthma exacerbations as well as during chronic therapy and prevent exacerbations from occurring during exercise

B₂-Agonists

these agents stimulate B₂-receptors, activating adenyl cyclase, which increases intracellular production of cyclic adenosine monophosphate (cAMP)

cAMP

Increased intracellular _____ and its activation results in bronchodilation, improved mucociliary clearance, and reduced inflammatory cell mediator release

B₂-receptors

Stimulation of _____ in skeletal muscle accounts for tremor

B₁-receptor

Agents with greater _____ affinity are more likely to cause cardiac effcts.

• inhalation

• Systemic

Whenever possible, agents should be administered via _____ to minimize systemic exposure and adverse reactions. ____ administration should be reserved for patients who cannot use inhalation therapy

• inhaled corticosteroid

• short-acting agent

Regimens with long-acting B₂-agonists should also include a concurrent _____, unless it is being used only to prevent EIB. All regimens containing long acting agents should also include a _____ for treatment of acute symptoms

• Nonselective B-agonists

• B₂-selective agents

______ may induce myocardial ischemia, myocardial necrosis, and arrhythmias because of excessive cardiac stimulation. Use of ______ is preferred

Tachyphylaxis

(form of tolerance) can occur with regular use of inhaled or oral B-agonists.

Paradoxical bronchoconstriction

____ found with B-agonists may be the result of a “cold freon effect” or the use of additives such as benzalkonium chloride in the formulation

• albuterol

• levalbuterol HCl

Unlike _____, which is a racemic mixture of albuterol’s R- and S-isomers, _____ is composed of the active R-enantiomer

• monoamine oxidase

• tricyclic antidepressants

• methyldopa

• aerosolized

Concomitant use of systemic B-agonists with _____ inhibitors, ______, or _____ may infrequently lead to severe hypertension. The risk with _____ agents may be smaller.

B-Adrenergic blockers

these agents precipitate bronchospasm and increase the dose of B-agonist necessary to achieve bronchodilation

B₁-Selective agents (metoprolol etc.)

these agents may be used carefully in asthma patients when the risk–benefit ratio indicates such as in an acute MI

B-Agonists

should not be combined with other sympathomimetic agents because of additive cardiovascular effects

epinephrine

Vasoconstrictor and vasopressor effects of _____ are antagonized by B-adrenergic blocking agents (e.g., phentolamine)

Corticosteroids

• these agents suppress the inflammatory response and decrease airway hyperresponsiveness

• bind to glucocorticoid receptors on the cytoplasm of cells

• activated receptor regulates transcription of target genes

• inhibition of transcription and release of inflammatory genes

• increased transcription of anti-inflammatory genes

Corticosteroids reduce inflammation via (2)

• Systemic corticosteroids

• 1-3

• 6-9

• Supplemental doses

_____ are used for rapid response during an exacerbation. Improvement in pulmonary function may begin within ___ to ___ hrs; however, the maximum effect is not achieved until ____ to ____ hrs. _____ should be administered to patients who are already taking systemic corticosteroids when they experience an exacerbation

Intravenous corticosteroids

administered to patients who are unable to take oral medications in severe exacerbations.

Oral corticosteroids

acceptable as emergency treatment if the patient can tolerate the oral route and is not believed to be in imminent danger of respiratory arrest

• prednisone

• prednisolone

most frequently used oral corticosteroids.

• prednisone

• prednisolone

• frequently administered in short “bursts” over 3 to 10 day to treat acute exacerbations

• This type of regimen may also be used to rapidly achieve asthma control.

serious acute exacerbations

Inhaled corticosteroids should not be used alone to treat ______

Inhaled steroids

preferred anti-inflammatory therapy for chronic asthma

Inhaled corticosteroids

first-line anti-inflammatory therapy for mild-to-severe persistent asthma in both adults and children

• severe: prednisone

• IV: methylprednisolone

• outpx burst therapy: prednisone

Treatment of asthma exacerbation in adults

• inpx tx, severe: prednisone, methylprednisolone, prednisolone

• outpx burst therapy: prednisone

Treatment of asthma exacerbation in children

Spacers

prescribed for patients who receive moderate-to-high doses of inhaled corticosteroids via MDIs.

• spacers

• gargle

interventions that minimize oropharyngeal drug deposition, local adverse reactions, and gastrointestinal absorption (2)

hepatic microsomal enzyme inducers

Concurrent use of _____ (e.g., rifampin, barbiturates, hydantoins) causes enhanced corticosteroid metabolism, reducing therapeutic efficacy.

corticosteroid clearance

Concurrent use of estrogens, oral contraceptives, itraconazole), or macrolide antibiotics (e.g., erythromycin, clarithromycin) may decrease _____

Cyclosporine

may increase the plasma concentration of corticosteroids

• potassium-depleting diuretics

• potassium

Administration of _____ (e.g., thiazides, furosemide) or other _____-depleting drugs (e.g., amphotericin) with corticosteroids causes enhanced hypokalemia.

digitalis glycosides

Serum potassium should be closely monitored, especially in patients on ______

Leukotriene modifiers

newest agents with anti-inflammatory properties to be approved for use in asthma