Resp (peds) Flashcards
LABA
Long-acting β2-selective agonists (LABA)
• Long Acting: peak effect 3 h
• Longer Duration, ~12 hours, of bronchodilating action as a result of high lipid solubility; dissolves in the smooth muscle cell membrane in high concentrations
• Salmeterol, Formoterol (Arformoterol, Vilanterol)
• Combination inhalers with ICS to improve asthma control,
not monotherapy for asthma
SABA
• Short Acting: peak effect 30-120 min
Inhaled albuterol, levalbuterol (Xopenex)
• Taken as-needed via MDI or nebulizer
• Indicated for status at increased doses and intervals
• Evaluate regular use of > 2 days/week (non EIB)
Levalbuterol (R-albuterol) – deliver at 1⁄2 the dose of albuterol with same efficacy
IV, SubQ Terbutaline; SubQ/IM Epinephrine
• Indicated for status unresponsive to inhaled
• Epinephrine stimulates α, β1, β2 receptors
• Higher risk of side effects; risk of arrhythmias
Lung Surfactants
• Prophylaxis: Treatment of Neonatal Respiratory Distress Syndrome (RDS)
• Surfactant deficiency increases surface tension leading to alveolar collapse and an increased WOB
• MOA: Replaces deficient or dysfunctional pulmonary surfactant;
reduces surface tension of alveolar
- Natural Surfactants
- Animal derived from bovine or porcine lungs
- Beractant (Survanta®); Calfactant (Infasurf®)
- Poractant Alfa (Curosurf®)
- Stored in refrigerator, must warm to room temperature without shaking
- Administer via endotracheal/intratracheal equally in 4 divided aliquots; alternating positions
- Dosed as mL/kg
- Monitoring parameters: apnea, bradycardia, oxygen desats
LABA Black Box
- In 2003 - safety of ICS/LABA was question after the analysis of an asthma study called Salmeterol Multicenter Asthma Research Trial (SMART.) showed a statistically significant increased risk of asthma-related deaths in patients on salmeterol
- In 2011 – FDA required drug companies to conduct trials to evaluate safety of LABAs when used in combination with ICS and FDA mandated label changes in all products containing LABAs used for asthma (not COPD) with a Black Box Warning
- On 12/2017 - FDA reviewed 4 large clinical safety trials (1/4 were in patients 4-11 years of age) which showed treating asthma with LABA/ICS does not result in significantly more serious asthma- related side effects than treatment with ICS alone and removed the Black Box Warning
SAMA + LAMA
Inhaled Anticholinergics or Antimuscarinic (SAMA; LAMA)
• MOA: Block action of acetylcholine in bronchial smooth muscle at muscarinic receptors (M1, M2, and M3 with equal affinity, but dissociates most rapidly from M2)
• Block contraction of airway smooth muscle and block increase in secretion of mucus that occurs in response to vagal activity
• Not as potent as beta agonists
SAMA – Ipratropium
• Indicated for initial therapy in the ED as combination therapy only (3 doses max)
• Monitoring: Xerostomia; URI; pharyngitis
Tiotropium
LAMA - Tiotropium
•Tiotropium
•Duration of therapy: ~25 hours •Dosed once daily
•GINA guidelines and recent NEJM trials
• Add-on tiotropium may be considered in patients > 12
years of age; for Step 5 already on a ICS/LABA
• Modestly improves lung function and modestly increases time to severe exacerbation requiring oral corticosteroids
Methylxanthines
- Theophylline, Aminophylline, Caffeine
- Theophylline most selective in its smooth muscle effects • Caffeine most marked central nervous system effects
- MOA: Respiratory center stimulation
- Improvement in respiratory muscle contraction
- Inhibit phosphodiesterase (PDE) enzymes, increasing cAMP and, in some tissues, cGMP - stimulates cardiac function, relaxation of smooth muscle, and reduction in the immune and inflammatory activity of specific cells.
- Inhibits cell surface receptors for adenosine (adenosine provokes smooth muscle contraction) and release of histamine from airway mast cells
- In neonates - decreased recovery time of fatigued muscles (associated with apnea)
Theophylline/Aminophylline
- Increased toxicities
- GI side effect, tremors, arrhythmias
- Requires for monitoring serum levels • Narrow therapeutic index
- Individual differences in metabolism
- Frequent drug-drug interactions
- Therapeutic trough levels 5–10 mcg/mL • Levels > 20 mcg/mL are considered toxic
- Do not use theophylline in conjunction with terbutaline - one or the other.
- RSI - ketamine used as a bronchodilator
Magnesium sulfate
Adjunctive Therapy for Status Asthmaticus:
• Magnesium sulfate
• Bronchodilator effects - relaxation of bronchial cells
• Magnesium decreases intracellular calcium by blocking its entry and its release from endoplasmic reticulum and by activating sodium-calcium pumps – results in muscle cell relaxation
• Magnesium stabilizes T cells and inhibits mast cell degranulation, leading to a reduction in inflammatory mediators
• Magnesium inhibits acetylcholine release
• Magnesium stimulates nitric oxide and prostacyclin synthesis, which might reduce asthma severity
• Infused over NO MORE than 20-30 minutes otherwise will lose bronchodilating properties; run over more than 30 min will result in hypotension
Corticosteroids (Glucocorticoids)
• MOA: Broad anti-inflammatory efficac; Inhibition of production of inflammatory cytokines - lymphocytes, eosinophils, mast cells
• Do not relax airway smooth muscle directly but reduce bronchial hyper-reactivity and reduce the frequency of asthma exacerbations if taken regularly
• Contract engorged vessels in bronchial mucosa and potentiate effects of β-agonists
• Clinical studies of corticosteroids consistently show
• Improvement in all indices of asthma control: severity of symptoms,
tests of airway caliber and bronchial reactivity, frequency of exacerbations, and quality of life
• PO/IV reserved for status or worsening symptoms despite high-dose maintenance therapy
• Short course 5–10 days of methylprednisolone or prednisolone • Hyperglycemia can be observed especially with first dose
• Oral Inhalation
Beclomethasone, Budesonide, Fluticasone, Mometasone
• Budesonide – only ICS available as nebulization formulation
• Major SE: oropharyngeal candidiasis and hoarseness with direct local effect on vocal cords
• May slow rate of growth by ~1 cm over first year of treatment, but not rate of growth thereafter, minimal effect on adult height
Leukotriene Modifiers
- MOA: Block interaction of leukotrienes with their receptors; and inhibit binding of LTD4 to its receptor
- Leukotrienes result from action of 5-lipoxygenase on arachidonic acid; and are synthesized by a variety of inflammatory cells in the airways (eosinophils, mast cells, macrophages, and basophils)
- Leukotriene B4 (LTB4) is a potent neutrophil chemoattractant, and LTC4 and LTD4 exert many effects known to occur in asthma, including bronchoconstriction, increased bronchial reactivity, mucosal edema, and mucus hypersecretion.
- Inhibition of 5-lipoxygenase, thereby preventing leukotriene synthesis; and inhibition of the binding of LTD4 to its receptor on target tissues, thereby preventing its action.
- Adult asthma does not have the same inflammatory/allergic response (“outgrowing” asthma), which necessitates these LT medications
Leukotriene Modifiers
Leukotriene receptor antagonists:
• Montelukast (Singulair) – allergic rhinitis, asthma
• Zafirlukast (Accolate) – asthma [not used often, assoc w/ hepatotoxicity]
- Accolate — Hepatotoxicity: Serious hepatic adverse events • CYP2C9 Inducer [drug-drug intx]
- Singulair — Neuropsychiatric events: Postmarketing reports of behavioral changes (eg, abnormal dreams, agitation, aggression, anxiety, attention deficit, depression, disorientation, hallucinations, hostility, insomnia, irritability, memory disturbances, restlessness, sleep disturbance, suicide ideation/behavior, and tremor) have been noted in pediatric, adolescent, and adult patients.
Montelukast (Singulair) • 12 months to 5 years: 4 mg qday • 6 to 14years: 5 mg qday • ≥15 years: 10 mg once daily • Dosed in the evening for asthma • Neuropsych effects
Zafirlukast (Accolate)
• Children 5 to 11 years: 10 mg twice daily
• Children ≥12 years and Adolescents: 20 mg twice daily
• Improve asthma control, reduce frequency of asthma exacerbations • Not as effective as low-dose ICS therapy
• Easier route of administration than aerosol inhalation
• Effective for allergic rhinitis
Cromolyn + Nedocromil
- Once widely used for asthma management, but not anymore
- MOA: Inhibit mast cell degranulation
- No direct bronchodilator action, but inhibit both antigen- and exercise-induced bronchospasm
Targeted Monoclonal Antibody Therapy
Antibody Name - [Isotype] - Target
Omalizumab - [Humanized IgG1] - IgE
Mepolizumab - [Humanized IgG1] - IL-5
Benralizumab - [Humanized IgG1] IL-5 receptor
Dupilumab - [Humanized IgG4] - IL-4 receptor
Ages ≥ 12 years
Restricted to patients with severe asthma and:
• Omalizumab - evidence of allergic sensitization
• Others – evidence of an eosinophilic phenotype
• Monitor for anaphylactic/hypersensitivity reactions
Targeted Monoclonal Antibody Therapy
• Administered subcutaneously q2-4 weeks depending on the antibody
Omalizumab
• Dose administered is adjusted for total IgE level and body weight
• MOA: A IgG monoclonal antibody which inhibits IgE binding to the high- affinity IgE receptor on mast cells and basophils
• Decreases bound IgE and limits activation and release of mediators in the allergic response (early and late phase)
Benralizumab, Mepolizumab
• A IgG1 monoclonal antibody that is an interleukin-5 antagonist; reduces
production and survival of eosinophils
Dupilumab
• A IgG1 monoclonal that inhibits interleukin-4 (IL-4) and interleukin-13 (IL-13) signaling; reduces production and survival of eosinophils
