Xanthines: Asthma, COPD & Apnea Management

Xanthines

• Xanthines are indicated for managing asthma, COPD, and apnea of prematurity in neonates.
• In COPD, xanthines are an alternative to inhaled bronchodilators but carry toxicity risks and offer limited benefit over B2 agonists and anticholinergic therapy.
• Caffeine citrate is the preferred agent for stimulating breathing in infants with apnea of prematurity.
• Caffeine citrate has better CSF penetration, a higher therapeutic index, and fewer side effects than theophylline.
• Individual theophylline metabolism rates vary, affecting dosage schedules and clearance rates.

Types and Trade Names of Xanthine Derivatives

• Theophylline, Oxtriphylline, Aminophylline, and Dyphylline are xanthine derivatives.
• Theophylline trade names include Theochron, Elixophyllin, and Theo-24.
• Oxtriphylline is marketed as Choledyl SA.
• Aminophylline's trade name is Aminophylline.
• Dyphylline is sold under the name Lufyllin.

Theophylline Mechanisms and Therapeutic Levels

• Theophylline's proposed mechanisms include phosphodiesterase inhibition and adenosine receptor blockade.
• Theophylline blood serum levels of less than 5 mcg/mL show no effects.
• The therapeutic range for theophylline is 10 to 20 mcg/mL.
• Nausea occurs with levels greater than 20 mcg/mL.
• Cardiac arrhythmias occur with levels greater than 30 mcg/mL.
• Seizures occur at levels of 40 to 45 mcg/mL.
• The recommended serum theophylline range for asthma is 5 to 15 mcg/mL.
• The recommended serum theophylline range for COPD is 5 to 10 mcg/mL.
• Theophylline can cause CNS adverse reactions such as headache, anxiety, restlessness, insomnia, tremor, and convulsions.
• Theophylline levels higher than 45 μg/mL can cause cardiac arrhythmias and seizures.
• Serum blood levels should be obtained 1 to 2 hours after an immediate-release theophylline administration.
• For sustained-release theophylline, serum blood levels should be measured 5 to 9 hours after the morning dose.

Adverse Reactions and Theophylline Metabolism

• Diuresis (Renal).
• Tachypnea (Respiratory).
• Nausea & Vomiting (Gastrointestinal).
• Anxiety & Headache (CNS).
• Palpitations (Cardiovascular).
• The diuretic effect of theophylline can cause dehydration and thickening of secretions in patients with bronchitis or cystic fibrosis; adequate fluid replacement is necessary.
• Theophylline is metabolized by the liver and excreted by the kidneys.
• Theophylline can be used for maintenance therapy in COPD if anticholinergics and β agonists cannot control the disease.

Guidelines and Effects of Theophylline

• Current guidelines suggest theophylline is not a first-line therapy for asthma or COPD.
• Long-acting β2 agonists give more consistent improvement in lung function over 12 hours in patients with COPD.
• A non-bronchodilating effect of theophylline is its ability to strengthen the diaphragm directly.
• Theophylline decreases cardiac output and increases pulmonary vascular resistance, increasing the heart's workload.
• Caffeine is better than theophylline for treating apnea of prematurity, because theophylline is a less potent respiratory system stimulator.
• The recommended loading dose for apnea of prematurity is 20mg/kg of caffeine citrate, equivalent to 10 mg/kg of caffeine.
• Non-bronchodilating effects of theophylline include increasing respiratory muscle contractility and endurance and cardiac output, decreasing pulmonary vascular resistance and improve myocardial muscle perfusion.

Key Terms Related to Mucus Control

• Gel: A pseudoplastic material with both viscosity and elasticity.
• Mucokinetic agent: Increases cough or ciliary clearance of secretions.
• Rheology: Study of deformation and flow of matter under stress.
• Expectorant: Increases the volume or hydration of airway secretions.
• Mucin: The main component of mucus.
• Viscosity: Resistance of a liquid to sheer forces.
• Mucolytic agent: Degrades polymers in secretions.
• Mucus: Secretion from goblet cells and submucosal glands, including water, proteins, and mucins.
• Mucoactive agent: Any drug affecting mucus secretion.
• Sputum: Expectorated secretions with respiratory tract, oropharyngeal, and inflammatory products.
• Mucoregulatory agent: Reduces the volume of airway mucus secretion.
• Elasticity: Rheologic property characteristic of solids.
• Mucospissic agent: Increases the viscosity of secretions.
• Glycoprotein: Protein that gives mucus its physical/chemical properties, such as viscoelasticity.
• Sol: The periciliary layer.
• Oligosaccharide: A monosaccharide
• Phlegm: Purulent material in the airways.

Beneficial Factors and Mucoactive Therapy

• Mucus benefits include protection, lubrication, waterproofing, defense against osmotic/inflammatory stress, and inhibition of chronic bacterial division.
• Mucoactive therapy should be considered after treatments that addresses infection and inflammation.
• N-acetylcysteine-l-cysteine (NAC) is used for bronchitis with a SVN dose of 3-5 mL.
• Dornase alfa is used for CF with a SVN dose of 2.5mg/amp, one ampoule daily.
• Aqueous water, saline (0.9%) is used for sputum induction and secretion mobilization with a dosage of SVN 3-5mL.
• Hyperosmolar saline 7% is used for airway clearance in CF with a SVN dose of 4mL. Delivered using an ultrasonic nebulizer.
• Dry powder mannitol is used for airway clearance in CF with a SVN dose of 4mL.
• 3% hyperosmolar saline is used for airway clearance in CF and infantile bronchiolitis with a SVN dose of 4mL.
• The two airway mucus layers are the gel layer and the periciliary layer.
• Mucus is a secretion from goblet cells and submucosal glands.
• Sputum comes from the respiratory tract, oropharyngeal, and nasopharyngeal areas.

Agents Affecting Ciliary Beat and Mucus Production

• α-Adrenergic agents, Cholinergic agents, and Methylxanthines increase ciliary beat and mucus production.
• Corticosteroids and Anticholinergics do not affect ciliary beat and mucus production.
• Factors slowing mucociliary transport include COPD/CF, airway drying, narcotics, endotracheal suction, tobacco smoke, atmospheric pollutants, and hyperoxia/hypoxia.
• Tobacco smoke is the most important predisposing factor to airway irritation and mucus hypersecretion.

Conditions and Diseases Affecting Mucus

• Chronic bronchitis is clinically defined as daily sputum expectoration for three months of the year for at least two consecutive years, usually in tobacco smokers or ex-smokers.
• Asthma is a chronic lung disease with inflammation and narrowing of the airways, and mucus hypersecretion during acute episodes.
• Bronchorrhea is the production of large volumes of watery sputum, and may respond to anti-inflammatory therapy.
• Plastic bronchitis is a rare disease with large, gelatinous, rigid branching airway casts.
• Cystic fibrosis (CF) is a hereditary disease with impaired CFTR protein function and chronic airway inflammation.
• Purulent sputum is difficult to cough up due to adhesive forces between the mucus and airway surface that severely reduces airflow (cough).
• Therapeutic options for controlling mucus hypersecretion besides mucoactive agents include removing causative factors and optimizing tracheobronchial clearance.
• Bronchiectasis is chronic airway inflammation and infection, leading to progressive pulmonary function decline.
• N-Acetyl-l-Cysteine (NAC) disrupts disulfide bonds and is more effective in alkaline pH environments (7.0 to 9.0).
• Bronchospasm from aerosolized NAC may be reduced by pretreatment with a rapid-onset bronchodilator.
• Dornase alfa should not be prescribed for patients with bronchiectasis and chronic obstructive pulmonary disease (COPD) because their secretions has a higher level of mucin (CF is mostly neutrophil).
• Hudson updraft II, Acorn II, and Pari LC Jet Plus with Pari inhaled boy compressor nebulizers and compressors have been approved for delivery of dornase alfa.
• Indications for Dornase Alfa include Management of CF, reduction of respiratory infections, preservation of lung function.
• Effectiveness of dornase alfa in a patient with CF can be evaluated by reduction in IV antibiotic use and hospitalizations, stability of lung function, reducing the number and severity of infectious exacerbation.
• Dornase alfa's brand name is Pulmozyme, with a dose of 2.5 mg daily.

Medications and Therapeutic Factors

• Guaifenesin marketed as Mucinex, is an expectorant that helps clear mucus from the airways.
• α Agonists can benefit diseases like asthma by increasing expiratory airflow.
• Long-term use of mucoregulatory medications like ipratropium is associated with a reduction in mucus secretion volume in patients with chronic bronchitis.
• Antiproteases can help restore the bacteria-killing capacity of neutrophils in diseases like cystic fibrosis.
• Hyperosmolar Saline improves mucociliary transport by inducing cough and hydrating airway surface fluids.
• 7% Hypertonic Saline Solution is a hyperosmolar therapy prescribed for CF patients, typically administered twice daily (bid).
• Causative Factors can be removed for controlling mucus hypersecretion.
• Tracheobronchial Clearance can be an optimization strategy for controlling mucus hypersecretion.
• Mucolytics such as NAC, help to break down mucus.
• CF Sputum has decreased mucin due to chronic bacterial infection.
• Neutrophils contribute to pus formation in the airways of CF patients.
• Treatments can affect Viscous mucus secretions in respiratory conditions.
• Adhesive Forces between mucus and airway surfaces make it difficult for patients with purulent sputum to cough it up.

Explore xanthines' role in managing asthma, COPD, and apnea, focusing on theophylline and caffeine citrate. Learn about their mechanisms, therapeutic levels, and the importance of monitoring due to variable metabolism rates. Discover trade names like Theochron and Choledyl SA.