Respiratory Pharmacology Study Notes

Autonomic Control of the Bronchi

Sympathetic Nervous System (Fight–Flight–Fright)

• Receptors: β₂ adrenergic receptors (Gₛ-coupled)

• Location: Bronchi, bronchioles

• Effect: Bronchodilation → more airflow for oxygenation

• Mechanism:

  • Gₛ → activates adenylate cyclase → ↑ cAMP

  • cAMP → activates Protein Kinase A (PKA)

  • PKA → inhibits myosin light-chain kinase (MLCK) → smooth muscle relaxation → bronchodilation

• Mnemonic:
  “You have one heart (β₁) and two lungs (β₂).”

Parasympathetic Nervous System (Rest–Digest)

• Receptors: M₃ muscarinic (Gq-coupled)

• Location: Bronchial smooth muscle, glands

• Effect: Bronchoconstriction and ↑ mucus secretion

• Mechanism:

  • Gq → activates phospholipase C (PLC) → IP₃ + DAG

  • IP₃ → ↑ intracellular Ca²⁺ → smooth muscle contraction

• Mnemonic:

  • Gq → Phospholipase C → IP₃ → Ca²⁺ → Contraction

  • “C for Calcium, C for Constriction.”

Muscarinic Drugs

Agonists

• Example: Methacholine (acts like acetylcholine)

• Mechanism: Stimulates M₃ → bronchoconstriction

• Clinical use: Methacholine challenge test → diagnostic for asthma (provocation test)

Antagonists

• Examples:

  • Ipratropium (short-acting)

  • Tiotropium (long-acting)

• Mechanism: Block M₃ → prevent bronchoconstriction → bronchodilation

• Uses: Asthma, COPD

• Mnemonic: “Drugs with -tropium block the tropic (parasympathetic) tone.”

β₂-Adrenergic Drugs

Short-Acting β₂ Agonists (SABA)

• Examples: Albuterol, Levalbuterol

• Use: Acute asthma rescue (rapid bronchodilation)

• Timing: Take before exercise in exercise-induced asthma

Long-Acting β₂ Agonists (LABA)

• Examples: Salmeterol, Formoterol

• Use: Maintenance therapy (chronic asthma)

• Key Rule: Never use LABA alone! → Must combine with inhaled corticosteroid (ICS)

• Side effects: Tremor, palpitations (β₁ spillover)

Corticosteroids

Inhaled Corticosteroids (ICS)

• Examples: Fluticasone, Budesonide

• Mechanism: Inhibit phospholipase A₂ → ↓ arachidonic acid → block both COX and LOX pathways

• Use: Maintenance therapy for persistent asthma

• Side effects: Oral candidiasis (rinse mouth after use)

Systemic Corticosteroids

• Examples: Prednisone (oral), Prednisolone (IV)

• Use: Severe or acute exacerbations

• Side effects: Weight gain, osteoporosis, Cushingoid features

Other Drug Classes in Asthma Treatment

1. Mast Cell Stabilizers

• Examples: Cromolyn sodium, Nedocromil

• Mechanism: Prevent mast cell degranulation → no histamine or leukotriene release

• Use: Prophylaxis for mild persistent asthma, allergy prevention

• Note: Not useful during acute attack

2. Methylxanthines

• Example: Theophylline, Aminophylline

• Mechanism:

  • Inhibits phosphodiesterase (PDE) → ↑ cAMP → bronchodilation

  • Antagonizes adenosine receptors (adenosine causes bronchoconstriction)

• Uses: Chronic asthma (rarely first-line due to toxicity)

• Side effects:

  • Narrow therapeutic index

  • Arrhythmia, seizures, CNS excitation

• Mnemonic:
  “Adenosine constricts — Theophylline dilates.”

3. Anti-Leukotrienes

a) LOX Inhibitors

• Example: Zileuton

• Mechanism: Inhibits 5-lipoxygenase → ↓ leukotriene synthesis

• Side effect: Hepatotoxicity, infections (↓ chemotaxis)

b) Leukotriene Receptor Antagonists

• Examples: Montelukast, Zafirlukast

• Mechanism: Block leukotriene D₄ receptor → prevent bronchoconstriction and inflammation

• Use: Aspirin-induced asthma, allergic asthma

• Side effect: Neuropsychiatric (e.g., depression, suicidal thoughts)

4. Monoclonal Antibodies (Anti-IgE)

• Example: Omalizumab

• Mechanism: Binds IgE → prevents mast cell activation

• Use: Severe allergic (extrinsic) asthma

• Note: Not useful for intrinsic (non-IgE) asthma

Asthma Pathophysiology Summary

Type	Mechanism	Example Triggers
Extrinsic (Allergic, Atopic)	Type I hypersensitivity (IgE-mediated)	Dust, pollen, dander
Intrinsic (Non-allergic)	Non-immunologic irritation	Cold air, infection, aspirin, stress, exercise

Key Events:

1. Allergen → Mast cell sensitization → Degranulation

2. Release of Histamine, PGD₂, Leukotrienes C₄/D₄ → bronchoconstriction + mucus

3. Chronic inflammation → airway remodeling

COPD Pharmacology

• First-line: β₂ agonists + antimuscarinics (bronchodilators)

• Ineffective drugs: Leukotriene modifiers (no role in COPD pathogenesis)

• New drug: Roflumilast (PDE-4 inhibitor) → ↑ cAMP → bronchodilation

• Adjunct therapy: Azithromycin (macrolide) for frequent exacerbations

• Vaccines: Pneumococcal + Influenza

Cystic Fibrosis Pharmacology

• Problem: Thick mucus due to defective CFTR → poor Cl⁻ transport

• Treatment:

  • CFTR potentiator: Ivacaftor (improves channel function)

  • Combination: Lumacaftor + Ivacaftor

  • Mucolytics: Inhaled hypertonic saline (draws water into mucus)

  • DNase therapy: Recombinant human DNase (breaks DNA in mucus)

  • Antibiotics: For infection control

  • Pancreatic enzyme replacement for exocrine insufficiency

Mnemonics & Quick Facts

Concept	Mnemonic
β₁ = heart, β₂ = lungs	“1 heart, 2 lungs”
M₃ → bronchoconstriction	“Gq = PLC → Ca²⁺ → Constriction”
SABA before exercise	“Short-acting before sprint”
Never LABA alone	“LABA needs a buddy (ICS)”
Theophylline effect	“Adenosine constricts, Theophylline dilates”
Asthma definition	“Bronchial hyperreactivity + mucus overproduction”
Aspirin-induced asthma	COX inhibition → ↑ leukotrienes
Mast cell stabilizers	Prevent degranulation (prophylaxis only)