4.2 Respiratory & Systemic Pharmacology

4.2 Respiratory & Systemic Pharmacology

Pediatric Respiratory Pharmacotherapy: Core Clinical Agents

Short-Acting Beta-2 Agonists (SABA)

1. Albuterol Sulfate (Racemic Albuterol):

   • Formulation: A 50:50 racemic mixture of the $(R)$-enantiomer (levalbuterol, active bronchodilator) and $(S)$-enantiomer (inactive, slow clearance, potentially pro-inflammatory and bronchoconstrictive).
   • Mechanism: Stimulates $\beta_2$-adrenergic receptors on airway smooth muscle, activating adenylate cyclase to increase cyclic adenosine monophosphate (cAMP), producing rapid relaxation of smooth muscle.
   • Intermittent Dosing: $2.5\text{ mg}$ nebulized ($0.5\text{ mL}$ of $0.5%$ solution diluted in normal saline) for patients $< 20\text{ kg}$; $5.0\text{ mg}$ for patients $\ge 20\text{ kg}$. pMDI dosing: 4 to 8 puffs with VHC every 20 minutes for 3 doses in acute exacerbations.
   • Continuous Nebulization for Status Asthmaticus: In severe pediatric asthma exacerbations refractory to intermittent therapy, continuous albuterol is administered at $10\text{ to }20\text{ mg/hr}$ using a specialized large-volume nebulizer (e.g., HOPE or HEART nebulizer).
   • Adverse Effects & Monitoring:
     • Tachycardia & Palpitations: Excessive $\beta_1$ stimulation and peripheral vasodilation-induced reflex tachycardia.
     • Tremors & Agitation: Peripheral $\beta_2$ skeletal muscle stimulation.
     • Hypokalemia: Direct stimulation of cell-membrane $\text{Na}^+/\text{K}^+$ ATPase pumps, driving potassium from extracellular fluid into intracellular compartments. Serum potassium must be monitored closely during continuous therapy.
     • Transient Hypoxemia: $\beta_2$-mediated pulmonary vasodilation in poorly ventilated lung segments overrides physiological hypoxic pulmonary vasoconstriction (HPV), temporarily worsening V/Q mismatch.

2. Levalbuterol (Xopenex):

   • Pure $(R)$-albuterol enantiomer.
   • Dosing: $0.31\text{ mg}$ (children 6–11 years), $0.63\text{ mg}$ to $1.25\text{ mg}$ TID. Generally considered equal in clinical efficacy to albuterol but preferred when patients develop severe dose-limiting tachycardia, tremors, or paradoxical bronchospasm with racemic albuterol.

Inhaled Anticholinergics (Muscarinic Antagonists)

• Ipratropium Bromide (Atrovent):
  • Mechanism: Competitive antagonist of muscarinic ($M_1, M_2, M_3$) acetylcholine receptors in bronchial smooth muscle, inhibiting cyclic guanosine monophosphate (cGMP) synthesis and blunting vagally mediated bronchoconstriction.
  • Dosing: $250\text{ }\mu\text{g}$ ($0.25\text{ mg}$) for children $< 20\text{ kg}$; $500\text{ }\mu\text{g}$ ($0.5\text{ mg}$) for children $\ge 20\text{ kg}$.
  • Clinical Role: Commonly added to a SABA during initial treatment of moderate-to-severe acute asthma; dose, repetition, care setting, and continuation follow the current asthma pathway. It provides synergistic bronchodilation and decreases hospital admission rates. Not indicated as maintenance monotherapy.

Inhaled Corticosteroids (ICS)

• Budesonide Suspension (Pulmicort Respules):
  • Mechanism: Potent anti-inflammatory glucocorticoid; suppresses cytokine production, reduces microvascular permeability, and upregulates $\beta_2$-receptor expression.
  • Asthma Maintenance Dosing: $0.25\text{ to }0.5\text{ mg}$ nebulized once or twice daily via jet nebulizer (cannot be delivered via ultrasonic nebulizers due to drug particle degradation).
  • Acute Viral Croup (Laryngotracheobronchitis): High-dose nebulized budesonide ($2.0\text{ mg}$ single dose) is an effective topical alternative or adjunct to systemic dexamethasone ($0.6\text{ mg/kg}$ oral/IV) for reducing subglottic mucosal edema.
  • Patient Care Rule: The face and mouth must be washed/rinsed after administration to prevent facial contact dermatitis and oral candidiasis (thrush).

Airway Clearance & Mucokinetic Agents

1. Hypertonic Saline (3% and 7% NaCl):

   • Mechanism: Creates an osmotic gradient that draws fluid from the submucosa into the airway lumen, rehydrating the dehydrated periciliary liquid layer. It disrupts ionic bonds within mucin polymers, decreases sputum viscosity, stimulates ciliary beat frequency, and provokes therapeutic coughing.
   • 3% NaCl: It is not routine emergency-department treatment for bronchiolitis. Some inpatient pathways may consider it, but evidence and recommendations vary; monitor for bronchospasm and clinical benefit.
   • 7% NaCl: Indicated for long-term maintenance in cystic fibrosis (CF).
   • Clinical precaution: Can cause bronchospasm. Assess airway reactivity and follow the disease-specific protocol; a bronchodilator is often given before nebulized acetylcysteine in susceptible patients.

2. Dornase Alfa (Pulmozyme / recombinant human DNase):

   • Mechanism: Sputum in cystic fibrosis is densely viscous due to high concentrations of extracellular polymerized DNA released by degenerating neutrophils during chronic infection. Dornase alfa is an engineered enzyme that selectively cleaves extracellular DNA into small fragments, drastically decreasing viscoelasticity without altering intact cell DNA.
   • Dosing: $2.5\text{ mg}$ once daily (or BID for advanced disease) nebulized via an approved nebulizer system (e.g., Pari LC Plus).
   • Critical Administration Rule: Dornase alfa is an active protein enzyme. It must NEVER be mixed or diluted with any other medication in the nebulizer cup (such as albuterol, hypertonic saline, or antibiotics). Chemical incompatibility and pH shifts denature the enzyme, completely destroying its mucolytic activity. It must be refrigerated at $2^\circ\text{C to }8^\circ\text{C}$ and protected from light.

Inhaled Antibiotics for Chronic Endobronchial Infections

Prescribed for chronic suppression of Pseudomonas aeruginosa colonization in cystic fibrosis:

• Inhaled Tobramycin (TOBI): Aminoglycoside; dosed at $300\text{ mg}$ nebulized BID (spaced 12 hours apart) in alternating cycles of 28 days ON therapy followed by 28 days OFF therapy. Also available as dry powder inhaler (TOBI Podhaler: four $28\text{ mg}$ capsules BID).
• Aztreonam Lysine (Cayston): Monobactam; dosed at $75\text{ mg}$ TID (minimum 4 hours apart) via the Altera nebulizer system in 28-day on/off cycles.
• Colistimethate Sodium (Colistin): Polymyxin antibiotic reserved for multi-drug resistant strains.

+------------------------------------------------------------------------------------------------+
|                    COMMON CYSTIC FIBROSIS TREATMENT SEQUENCE                                  |
+------------------------------------------------------------------------------------------------+
| 1. SABA (Albuterol)             --> Dilates airways, prevents bronchospasm from hypertonic soln|
+------------------------------------------------------------------------------------------------+
| 2. Hypertonic Saline            --> Hydrates airway surface before or during clearance         |
+------------------------------------------------------------------------------------------------+
| 3. Airway Clearance / Dornase   --> Sequence and dornase timing follow the individual plan      |
+------------------------------------------------------------------------------------------------+
| 4. Inhaled Antibiotic (TOBI)    --> DEPOSITED LAST onto cleared mucosal surface for max dwell  |
+------------------------------------------------------------------------------------------------+

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Worked Clinical Calculation: Continuous Albuterol Delivery

Clinical Scenario

A 6-year-old child ($22\text{ kg}$) presents to the pediatric emergency department with acute status asthmaticus refractory to three intermittent nebulizer treatments. The physician orders continuous albuterol nebulization at $15\text{ mg/hr}$ for 4 hours using a specialized high-output large-volume nebulizer. The nebulizer operates with a continuous liquid output rate of $30\text{ mL/hr}$ at $10\text{ L/min}$ driving flow. Stock albuterol is available as a $0.5%$ solution ($5\text{ mg/mL}$).

Step-by-Step Formulation Calculation

1. Calculate total albuterol dose required for the 4-hour run: $\text{Total Drug} = 15\text{ mg/hr} \times 4\text{ hours} = 60\text{ mg albuterol}$

2. Calculate volume of 0.5% albuterol stock solution needed: $\text{Volume of Drug} = \frac{60\text{ mg}}{5\text{ mg/mL}} = 12.0\text{ mL of } 0.5\%\text{ albuterol}$

3. Calculate total fluid volume delivered by nebulizer over 4 hours: $\text{Total Solution Volume} = 30\text{ mL/hr} \times 4\text{ hours} = 120.0\text{ mL}$

4. Calculate volume of normal saline diluent to add: $\text{Diluent Volume} = 120.0\text{ mL (total)} - 12.0\text{ mL (albuterol)} = 108.0\text{ mL normal saline}$

Clinical Action: The therapist mixes $12.0\text{ mL}$ of $0.5%$ albuterol with $108.0\text{ mL}$ of $0.9%$ NaCl in the reservoir, initiates gas flow at $10\text{ L/min}$, and places the child on continuous cardiac monitoring and serial electrolyte checks for hypokalemia.

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NPS Exam Traps

Exam Trap 1: The "Crying Infant" Fallacy

A common clinical vignette presents an infant screaming during aerosol administration, asking whether to continue because "crying forces deep breathing." Crying drastically decreases lung deposition by $>80%$. High expiratory flow rates and brief, turbulent gasps cause almost the entire dose to impact in the upper pharynx. The examination answer is to pause the treatment, calm the infant with parental soothing or a pacifier, or deliver the aerosol via pMDI-VHC while the infant sleeps.

Exam Trap 2: Mixing Dornase Alfa in the Nebulizer Cup

An exam question may suggest combining dornase alfa (Pulmozyme) with albuterol or tobramycin to "save time" or "reduce patient fatigue." Dornase alfa must NEVER be mixed with other medications. Doing so alters the biochemical pH and ionic environment, denaturing the recombinant DNase enzyme and rendering it biologically inert.

Exam Trap 3: Jet Nebulizer Flow on Mechanical Ventilators

When delivering aerosolized medication to an intubated neonate on a mechanical ventilator, using a small-volume jet nebulizer powered by an external 50 psig flowmeter adds $6\text{ to }8\text{ L/min}$ of unmeasured gas. In an infant with a tidal volume of $10\text{ mL}$, this extra flow causes severe volutrauma, inadvertent PEEP spikes, and auto-triggering. The correct intervention is to utilize an in-line vibrating mesh nebulizer (VMN) or an integrated ventilator nebulizer function that synchronizes flow during the inspiratory phase without altering base flow.