Respiratory Pharmacology & Related Concepts

Respiratory Disease Spectrum

• Disorders range from benign (e.g., common cold) to life-threatening conditions (e.g., bacterial pneumonia, pulmonary embolism, lung cancer). These conditions can affect the airways, parenchyma, or pleura.

• Pharmacology in respiratory care therefore spans a broad range of drug classes, including respiratory stimulants, bronchodilators, anti-inflammatories, mucolytics, antitussives, decongestants, and smoking-cessation aids, each targeting specific symptoms or underlying pathologies.

Chronic Obstructive Pulmonary Disease (COPD)

• COPD is a composite of two progressive and often co-existing pathologies, characterized by persistent airflow limitation that is usually progressive and associated with an enhanced chronic inflammatory response in the airways and the lung to noxious particles or gases: • Chronic bronchitis:

  • Defined clinically by a chronic productive cough for at least 3 months in each of 2 consecutive years.

  • Involves inflammation and swelling of the bronchial lining, leading to hypertrophy of mucus-secreting glands, chronic mucus hypersecretion, and a productive "wet" cough.

  • Airway obstruction is primarily due to mucus plugging, inflammation, and some bronchospasm.
    • Emphysema:

  • Defined pathologically by abnormal, permanent enlargement of the air spaces distal to the terminal bronchioles, accompanied by destruction of their walls without obvious fibrosis.

  • This destruction of alveolar sacs ("lung grapes") significantly decreases the total surface area available for gas exchange, leading to exertional dyspnea (shortness of breath with activity).

• Etiology: Cigarette smoking is the PRIMARY and most significant cause, responsible for approximately 80-90\% of COPD cases. Other risk factors include exposure to occupational dusts and chemicals, air pollution, and genetic factors (e.g., alpha-1 antitrypsin deficiency).

• Patient Education: Emphasize that COPD is largely irreversible and progressive. Cessation of smoking is the single most effective intervention to slow the rate of decline in lung function and improve quality of life, although it does not reverse existing damage.

Oxygen Therapy

• Indications: Used to treat hypoxemia (low blood oxygen levels) resulting from various conditions, including COPD exacerbations, severe heart or lung disease, smoke inhalation, carbon monoxide or cyanide poisoning, and central nervous system depression leading to hypoventilation.

• Delivery Methods: Oxygen can be delivered via a variety of devices, chosen based on the patient's oxygen requirements, comfort, and clinical situation:

  • Endotracheal tube (for intubated patients)

  • Nasal cannula (1-6\text{ L/min})

  • Simple face masks (5-10\text{ L/min})

  • Venturi masks (provide precise FiO₂)

  • T-pieces (for tracheostomies or endotracheal tubes)

  • Oxygen tents or hoods (primarily for pediatric patients)

• Side Effect of High FiO₂: In patients with chronic hypercapnia (CO₂ retainers, typically those with severe COPD), high concentrations of supplemental oxygen (high FiO₂) can suppress the hypoxic drive, leading to hypoventilation and worsening hypercapnia (CO₂ narcosis). Careful monitoring and titration of oxygen are crucial.

• Fire Risk: Oxygen itself is not flammable but is a potent oxidizer and strongly SUPPORTS combustion. Any open flame, spark, or heat source in an oxygen-rich environment dramatically increases the risk of fire. Anecdotal evidence includes a smoking patient igniting oxygen tubing, leading to severe burns to the airway.

Respiratory Stimulants

• Caffeine citrate: Primarily used for neonatal apnea of prematurity. Its mechanism involves antagonism of adenosine receptors, which helps stimulate the central respiratory drive in premature infants.

• Theophylline (IV or PO): An older medication option used for infant apnea. It is also classified as a xanthine bronchodilator due to its broader effects on respiratory smooth muscle. Its use in adults is limited due to a narrow therapeutic index.

Bronchodilators – General

• Action: These medications work by relaxing the bronchial smooth muscle, which leads to bronchodilation (widening of the airways). This decreases bronchospasm, reduces airway resistance, and consequently lessens the work of breathing, improving airflow to the lungs.

• Routes: Available via oral (PO), parenteral (IV/IM), and inhalation routes. Inhalation is generally preferred as it delivers the drug directly to the airways, resulting in a faster onset of action and significantly fewer systemic adverse drug reactions (ADRs) compared to oral or parenteral routes.

Inhalation Devices

• Metered-Dose Inhalers (MDI):
  • A press-and-inhale valve system that delivers a specific dose of aerosolized medication with each actuation. It requires careful coordination between pressing the canister and inhaling simultaneously for optimal drug delivery.
  • Cleaning: To maintain efficacy and prevent clogging, remove the metal canister from the plastic actuator. Rinse the plastic mouthpiece thoroughly for approximately 30 seconds under warm running water. Invert and flush the actuator, then allow it to air-dry completely overnight before reassembly. Cleaning should be done regularly, usually once a week.

• Dry-Powder Inhalers (DPI):
  • These devices deliver medication as a dry powder, typically without a propellant. They are breath-actuated, meaning the drug is dispersed by the patient's own inspiratory flow. Therefore, patients must be able to generate an adequate and forceful inspiratory effort to draw the powder into their lungs effectively.
  • Commonly used for corticosteroids and long-acting beta-agonist (LABA) combinations (e.g., Advair, Symbicort).

• Small-Volume Nebulizers (SVN):
  • Aerosolize liquid drug formulations (e.g., albuterol solution) into a fine mist using compressed air or oxygen. The mist is then inhaled through a mask or mouthpiece, allowing for deep penetration into the lungs. They are particularly useful in acute settings, for patients unable to coordinate MDIs, or for pediatric patients.

Sympathomimetic (Adrenergic) β₂-Agonists

• Mechanism of Action (MOA): These drugs selectively stimulate beta-2 adrenergic receptors located on bronchial smooth muscle. Activation of these receptors leads to increased intracellular cyclic AMP (cAMP), which relaxes smooth muscle and causes bronchodilation.

• Classification:
  • SABA (short-acting β₂-agonists) – e.g., Albuterol Sulfate ( Proventil HFA), Levalbuterol (Xopenex). These are the drug of choice for acute asthma flares and exercise-induced bronchospasm due to their rapid onset (within minutes) and relatively short duration of action (4-6 hours).
  • LABA (long-acting β₂-agonists) – e.g., Salmeterol, Formoterol. These agents provide sustained bronchodilation (12-24 hours) and are used for maintenance therapy in COPD and asthma, particularly when combined with inhaled corticosteroids. LABAs are NOT for rescue use in acute exacerbations due to their slower onset of action.

• Patient-Teaching “Rescue Inhaler Rules”:
  • Patients should be instructed to use their SABA rescue inhaler (e.g., albuterol) no more than twice per week for symptoms. Increasing use beyond this frequency (e.g., using it daily or multiple times a day) indicates deteriorating asthma or COPD control and necessitates a prompt visit to their healthcare provider for evaluation and adjustment of their maintenance regimen.
  • Overuse ADRs: Due to systemic absorption, excessive use can lead to dose-related adverse effects, including tachycardia (increased heart rate), palpitations, tremors (especially in the hands), anxiety, nervousness, insomnia, and hypokalemia.

Anticholinergic Bronchodilators

• Tiotropium (Spiriva) DPI: A long-acting anticholinergic (LAMA) commonly used for daily maintenance therapy of bronchospasm associated with COPD. Other examples include Ipratropium (short-acting) and Aclidinium.

• Mechanism of Action (MOA): These medications act as parasympatholytics by blocking muscarinic (M₃) receptors on bronchial smooth muscle, which prevents acetylcholine from inducing bronchoconstriction and mucus secretion. This leads to bronchodilation.

• Clinical Use: While effective for long-term control, they are generally not used for acute relief of bronchospasm because their onset of action is slower than SABAs.

Xanthines

• Theophylline:
  • Mechanism of Action (MOA): Primarily causes bronchodilation by inhibiting phosphodiesterase enzymes, which leads to an increase in intracellular cyclic AMP (cAMP) and subsequent relaxation of bronchial smooth muscle. It also has anti-inflammatory properties and can enhance diaphragmatic contractility.
  • Therapeutic Monitoring: Due to its narrow therapeutic index (small difference between therapeutic and toxic doses), serum level monitoring was formerly routine to prevent toxicity (e.g., arrhythmias, seizures). Current guidelines reserve its use for COPD patients whose symptoms remain refractory despite optimal inhaled LABA/LAMA therapy. Monitoring is still essential when used.

Patient Education for Bronchodilators

• Differentiate RESCUE vs MAINTENANCE Inhalers: Crucially educate patients on the distinct roles of their inhalers. Rescue inhalers (SABAs) are for immediate symptom relief, while maintenance inhalers (LABAs, LAMAs, ICS) are for daily, long-term control and prevention of symptoms.

• Demonstrate Device Technique: Provide detailed, hands-on demonstration of proper inhaler technique (MDI, DPI, SVN). Encourage return demonstration to ensure proficiency. Recommend the use of a spacer device with MDIs, especially for patients with poor hand-breath coordination, as it improves drug delivery to the lungs and reduces oral deposition.

• Hydration: Emphasize the importance of adequate systemic hydration (goal fluid intake ~8\text{ cups} \times 8\text{ oz} = 64\text{ oz/day} unless medically contraindicated like in severe heart failure). Proper hydration helps to mobilize and thin respiratory mucus, making it easier to clear from the airways.

Anti-Inflammatory Respiratory Drugs

Corticosteroids

• Mechanism of Action (MOA): Potent anti-inflammatory agents that work by suppressing the inflammatory response in the airways. They reduce airway hyperresponsiveness, decrease mucus production, and inhibit the migration and activation of inflammatory cells (e.g., eosinophils, mast cells). For short “burst”

• Systemic Corticosteroids: Oral corticosteroids (e.g., Prednisone) are prescribed as a short-term "burst/taper" regimen (e.g., starting at 40-60\text{ mg/day} decreasing over 5-7 days) for severe asthma or COPD exacerbations to quickly reduce inflammation. Prolonged systemic use carries significant risks of systemic adverse effects.

• Inhaled Corticosteroids (ICS): These are the cornerstone of long-term asthma prophylaxis and maintenance therapy for patients with persistent asthma , budesonide (Pulmicort Flexhaler), beclomethasone, mometasone). They deliver anti-inflammatory action directly to the airways, minimizing systemic absorption.

• Oral Candidiasis Prevention: Patients using ICS must be instructed to rinse their mouth thoroughly and spit out the water immediately after each dose. This prevents local deposition of the steroid, which can lead to oral candidiasis (thrush) or esophageal colonization due to immunosuppression of local flora.

• Intranasal Sprays: Used for allergic rhinitis and non-infectious rhinitis (e.g., fluticasone (Flonase), triamcinolone (Nasacort)). For maximal efficacy, patients should begin using them often before the typical allergen season begins to build up their anti-inflammatory effect. Side effect- throat irritation and hoarseness

• Adverse Drug Reactions (ADR): Common local ADRs include throat irritation, hoarseness (dysphonia), and coughing due to direct contact with the vocal cords. Systemic effects are less common with recommended ICS doses but can occur with high doses or prolonged use (e.g., bone density loss, cataracts).

Leukotriene Modifiers

• Examples: Montelukast (Singulair), Zafirlukast (Accolate), Zileuton.

• Side effects- headaches

• Routes: Administered orally (PO).

• Mechanism of Action (MOA): These drugs either block leukotriene receptors (e.g., montelukast, zafirlukast – leukotriene receptor antagonists) or inhibit leukotriene synthesis (e.g., zileuton). Leukotrienes are potent inflammatory mediators that contribute to bronchoconstriction, airway edema, mucus secretion, and eosinophil recruitment in asthma. By blocking their effects, these drugs help with asthma prophylaxis and chronic control.

• Adverse Drug Reactions (ADR): Headache is the most common side effect. Rarely, neuropsychiatric events (e.g., agitation, depression, suicidal thoughts) have been reported with montelukast, warranting caution and patient monitoring.

Mast Cell Stabilizer

• Cromolyn sodium: Available as an inhaler or nasal spray.

• Mechanism of Action (MOA): Acts locally in the lungs (or nose) to prevent the degranulation of mast cells, thereby inhibiting the release of inflammatory mediators (e.g., histamine, leukotrienes) that initiate the allergic response. It is strictly prophylactic and has no bronchodilator activity or role in acute attacks.

Mucolytics & Expectorants

• Mucolytics: Work by chemically breaking down the disulfide bonds within mucus proteins, making thick respiratory secretions thinner and less viscous. This action facilitates their removal by coughing or suctioning. They are particularly useful in conditions with tenacious secretions such as COPD, cystic fibrosis, and pneumonia. Acetylcysteine (Mucomyst) is an example, which can also be an antidote for acetaminophen overdose.

• Expectorant: Guaifenesin (Mucinex):
  • Mechanism of Action (MOA): Increases the volume of respiratory tract fluids and decreases the viscosity of sputum, making it easier to expel. It effectively hydrates the mucus.
  • Patient Education: Patients MUST maintain normal systemic hydration to achieve the desired effect of guaifenesin. Emphasize that excessive fluid intake beyond normal daily needs is unnecessary and does not enhance its efficacy if the patient is already well-hydrated.

Antitussives

• Action: Medications used to suppress or relieve cough.

• Narcotic Antitussives: Codeine and hydrocodone (often in combinations with antihistamines or decongestants) are potent cough suppressants due to their direct action on the cough center in the medulla oblongata. However, they carry risks of respiratory depression, sedation, constipation, and euphoria/abuse potential. Their use should be limited, especially in at-risk populations.

• Non-narcotic Antitussives: Dextromethorphan (DM) is a common active ingredient in many over-the-counter cough remedies. It works centrally to suppress the cough reflex, but without the significant respiratory depression or abuse potential of opioids. It is generally considered safe for children aged 4 years and older.

• Benzonatate (Tessalon Pearls): Works locally as a non-opioid by anesthetizing the stretch receptors within the respiratory passages, lungs, and pleura, thereby reducing the stimuli that initiate the cough reflex.

• Side effects- respiratory depression

Antihistamines

• Mechanism of Action (MOA): These drugs exert their effects primarily through H₁ receptor blockade, preventing histamine from binding to its receptors and mediating allergic symptoms. This action leads to decreased capillary permeability, reduced edema, diminished pruritus (itching), and decreased mucus secretion.

• 1st Generation Antihistamines: Diphenhydramine (Benadryl), Chlorpheniramine.
  • Uses: Broad applications beyond allergy relief, including use as an antitussive, antiemetic, and a common ingredient in over-the-counter "PM" products for sleep aid due to their significant sedative properties.
  • Side effects- Characterized by pronounced anticholinergic adverse effects, often referred to as "drying" effects (e.g., dry eyes, dry mouth, urinary retention, constipation, blurred vision). They also cause significant sedation, drowsiness, a "hangover" effect the next day, and potential for tolerance development with prolonged use.
  • Ethical Pearl: Avoid using these medications as a routine pediatric sedative due to potential for paradoxical excitation in children and safety concerns.

• 2nd Generation Antihistamines: Loratadine (Claritin), Cetirizine (Zyrtec), Fexofenadine (Allegra).
  • Advantages: Developed to be less sedating and have fewer anticholinergic effects compared to first-generation agents. They achieve this by being less able to cross the blood-brain barrier and having greater selectivity for peripheral H₁ receptors.
  • Duration: Typically offer a longer duration of action (\sim 24 hours), allowing for once-daily dosing.

Decongestants (α-Adrenergic Vasoconstrictors)

• Mechanism of Action (MOA): These agents are alpha-adrenergic agonists that cause vasoconstriction of the blood vessels in the nasal mucosa. This reduces blood flow, leading to shrinkage of swollen nasal membranes and improved airflow through the nasal passages.

• Examples: Pseudoephedrine (oral), Phenylephrine (oral, topical nasal spray), Oxymetazoline (topical nasal spray).

• Adverse Drug Reactions (ADRs): Due to their systemic vasoconstrictive effects, oral decongestants can cause hypertension. They are contraindicated or should be used with extreme caution in patients with uncontrolled hypertension, severe cardiovascular disease, hyperthyroidism, glaucoma, or diabetes unless cleared by a healthcare provider.

• Rebound Congestion (Rhinitis Medicamentosa):
  • A serious concern with topical nasal decongestant sprays (e.g., oxymetazoline). Prolonged or excessive use leads to a cycle of progressively worsening congestion as the effects wear off. This phenomenon is caused by mucosal ischemia and damage from chronic vasoconstriction.
  • Prevention: Patients must be strictly advised to limit intranasal decongestant use to no more than 3 consecutive days. Oral decongestants should generally not be used for more than 7 days due to the risk of systemic ADRs. Anecdotes, like a patient's NyQuil overuse leading to rebound congestion and persistent throat clearing, highlight this risk.

OTC Cold/Allergy Product Safety

• Risk of Overdose: Many over-the-counter (OTC) combination cold and allergy formulas contain identical active ingredients (e.g., multiple decongestants, acetaminophen). Without careful label reading, patients risk cumulative overdose by taking multiple products simultaneously.

• Standardized Labels: ALWAYS compare and scrutinize the active-ingredient panels, which are now standardized on all OTC labels, to prevent accidental double-dosing.

• Pediatric Vigilance: Apply the same vigilance and caution when administering OTC products to children, ensuring age-appropriate dosing and avoiding multiple products with overlapping ingredients.

Herbals & Drug Interactions

• Importance of Disclosure: Patients often omit listing herbal supplements, dietary supplements, or "natural" remedies (e.g., St. John’s Wort, echinacea, ginkgo biloba) when asked about their medications. This omission poses a significant risk as many herbals can have clinically relevant and potentially dangerous interactions with prescription medications, affecting efficacy or increasing toxicity (e.g., St. John's Wort can interact with cardiac medications, SSRIs, oral contraceptives, and anticoagulants).

• Comprehensive Medication Reconciliation: Healthcare providers must conduct a thorough medication reconciliation process that explicitly includes "medications, herbs, vitamins, and all other supplements" to identify potential interactions and ensure patient safety.

Smoking-Cessation Pharmacology

• Efficacy: Combining behavioral counseling and support with pharmacologic aid has been demonstrably shown to approximately double quit rates compared to attempting to quit "cold turkey" alone.

Nicotine Replacement Therapy (NRT)

• Forms: Available in various forms, including gum (Nicorette), lozenges (Commit), transdermal patch (Nicoderm CQ), inhaler, and nasal spray (Nicotrol).

• Mechanism: Provide controlled, graduated levels of nicotine to the body, which helps to attenuate physical withdrawal symptoms (e.g., irritability, anxiety, difficulty concentrating, cravings) that occur when individuals stop smoking. The goal is to gradually reduce nicotine dependence.

• Patch ADR: A notable adverse effect of the nicotine patch can be vivid or disturbing dreams. Patients should be warned about this possibility, and if distressing, they may be advised to remove the patch before bedtime.

Non-Nicotine Prescription Aids

• Bupropion SR (Wellbutrin®/Zyban®):
  • An atypical antidepressant that is thought to aid in smoking cessation by inhibiting the reuptake of dopamine and norepinephrine in the brain, which helps to reduce nicotine cravings and withdrawal symptoms. It can also enhance mood, which is beneficial during the quitting process.
  • Contraindications: History of seizures or eating disorders.

• Varenicline (Chantix®):
  • A partial nicotine receptor agonist/antagonist. It works by binding to nicotine acetylcholine receptors (specifically the \alpha4\beta2 subtype) in the brain. This partial agonism helps to reduce nicotine withdrawal symptoms, while its antagonist activity blocks nicotine from binding, thereby reducing the reward and pleasure associated with smoking if the person slips up.
  • Monitoring: Close monitoring for mood changes, agitation, depression, and suicidality is crucial. There have been post-marketing reports linking varenicline use to serious neuropsychiatric events (e.g., personal anecdote of 2 suicide attempts linked to its use by a patient), although research is ongoing regarding the definitive causal link.

Electronic Cigarettes (E-cigarettes)

• Mechanism: Deliver vaporized nicotine and other chemicals (e.g., flavorings, propylene glycol, vegetable glycerin) without the combustion products found in traditional cigarettes. While they may produce less odor and contain fewer toxins than conventional cigarettes, the long-term pulmonary and cardiovascular risks are still largely under study and not fully understood. There is growing concern about their potential for addiction, exposure to carcinogens (e.g., formaldehyde), and lung injuries (e.g., EVALI - e-cigarette or vaping product use-associated lung injury).

Key Patient-Education & Ethical Pearls

• Inhaler/Nebulizer Technique: Always demonstrate proper inhaler and nebulizer technique for patients and verify their understanding through return demonstration. Emphasize that improper usage, as seen in a video where a patient misused an MDI and emptied a canister per week, can severely compromise drug delivery and therapeutic outcomes.

• Device Spacing & Cleaning: Teach patients the importance of proper spacing between inhaler actuations and regular cleaning of inhalation devices (MDIs, nebulizers) to prevent drug crystallization, blockages, and potential bacterial/fungal growth leading to infection.

• Inhaler Sequence: When both a bronchodilator and an inhaled corticosteroid are prescribed, clarify the correct sequence: "Bronchodilator FIRST, then corticosteroid." The bronchodilator opens the airways, allowing the corticosteroid to penetrate deeper and more effectively into the lungs.

• Oxygen Fire Safety: Issue a clear and absolute warning to oxygen users about the strict no-smoking standard and the avoidance of any open flames or heat sources near oxygen equipment, reiterating that oxygen strongly supports combustion and poses a significant fire risk.

• Pediatric Sedation: Limit children’s exposure to sedating antihistamines (1st generation) and never administer them solely for caregiver convenience to induce sleep, due to the risk of paradoxical effects, over-sedation, and other adverse events.

• OTC & Herbal Vigilance: Instruct patients to meticulously read ALL over-the-counter (OTC) and herbal product labels. Advise them to consult their healthcare provider or pharmacist, especially if they have chronic diseases (e.g., cardiac conditions, thyroid disorders, diabetes), to avoid dangerous drug interactions or contraindications.

• Holistic Management: Emphasize that pharmacologic success in respiratory conditions is integral to, but not solely dependent on, medication. Lifestyle factors such as adequate hydration, regular exercise (as tolerated), and most importantly, smoking cessation, are crucial components of comprehensive disease management and overall well-being.

Need to know

oxygen therapy

• Side effects- hypo ventilation- of oxygen delivered at too high a concentration or for prolonged periods of time without proper monitoring

• Precautions- for when oxygen is used- is combustible

Mucolytics and Expectorants

• Mucolytics- decrease the hyper secretion of and liquefy pulmonary secretions

• Expectorants- such as guaifenesin(the only agent aprroved for use as an expectorant). Adequate fluid intake is important to maintain normal fluid volume, but excessive fluid intake is of no value. Guaifenesin is commonly combined in cough syrups for symptomatic management of productive (wet) coughs associated with upper respiratory tract infections, bronchitis, pharyngitis, influenza and measles or coughs provoked by sinusitis. Guaifenesin/ mucinex