Asthma and COPD drugs, mechanism of action, side effects
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I've exhausted my database queries. I have the drug lists from Katzung and respiratory textbook content. Let me now compile the comprehensive answer from what I retrieved plus my medical knowledge.
Asthma & COPD Drugs: Mechanisms of Action and Side Effects
Drug Classes Overview
| Class | Examples | Primary Use |
|---|---|---|
| Short-acting β₂ agonists (SABA) | Albuterol, terbutaline, levalbuterol | Asthma/COPD rescue |
| Long-acting β₂ agonists (LABA) | Salmeterol, formoterol, indacaterol, vilanterol, olodaterol | Asthma/COPD maintenance |
| Short-acting muscarinic antagonists (SAMA) | Ipratropium | COPD rescue, asthma adjunct |
| Long-acting muscarinic antagonists (LAMA) | Tiotropium, aclidinium, umeclidinium, glycopyrrolate, revefenacin | COPD maintenance |
| Inhaled corticosteroids (ICS) | Fluticasone, budesonide, beclomethasone, mometasone, ciclesonide | Asthma controller; COPD add-on |
| Methylxanthines | Theophylline, aminophylline | Asthma/COPD adjunct |
| Leukotriene modifiers | Montelukast, zafirlukast, zileuton | Asthma controller |
| Mast cell stabilizers | Cromolyn sodium, nedocromil | Asthma prophylaxis |
| Biologics | Omalizumab, mepolizumab, benralizumab, dupilumab | Severe asthma |
| PDE4 inhibitors | Roflumilast | Severe COPD |
1. Beta₂ Agonists (SABAs and LABAs)
Mechanism of Action
β₂ adrenergic receptors on airway smooth muscle cells are Gs-coupled. Agonist binding → adenylyl cyclase activation → ↑ cAMP → protein kinase A activation → phosphorylation of myosin light-chain kinase (inactivating it) and opening of Ca²⁺-activated K⁺ channels → smooth muscle relaxation → bronchodilation.
Additional effects include:
- Inhibition of mast cell mediator release
- Increased mucociliary clearance
- Decreased microvascular permeability
SABAs (albuterol, terbutaline): onset 5–15 min, duration 4–6 h → rescue bronchodilation
LABAs (salmeterol, formoterol): duration 12 h; formoterol also has rapid onset (can be used rescue in some regimens). Indacaterol, vilanterol, olodaterol are ultra-LABAs (once daily, COPD primarily).
LABAs (salmeterol, formoterol): duration 12 h; formoterol also has rapid onset (can be used rescue in some regimens). Indacaterol, vilanterol, olodaterol are ultra-LABAs (once daily, COPD primarily).
Side Effects
| Effect | Mechanism |
|---|---|
| Tachycardia, palpitations | β₁ cross-stimulation |
| Tremor (fine, skeletal muscle) | β₂ receptors on skeletal muscle |
| Hypokalemia | β₂-mediated K⁺ uptake into cells |
| Hyperglycemia | Hepatic glycogenolysis (β₂) |
| Headache, nervousness | CNS stimulation |
| Paradoxical bronchospasm (rare) | Hypersensitivity to propellant or drug |
| ⚠️ LABA monotherapy contraindicated in asthma | Increased asthma-related deaths (black box warning); must combine with ICS |
Katzung's Basic and Clinical Pharmacology, 16th Ed.
2. Muscarinic Antagonists (SAMA / LAMA)
Mechanism of Action
Airway smooth muscle and glands receive cholinergic (M₃ receptor) innervation via the vagus nerve. Muscarinic antagonists competitively block M₃ receptors → inhibit acetylcholine-mediated bronchoconstriction and reduce mucus secretion.
Ipratropium (SAMA): non-selective (M₁, M₂, M₃); onset ~15 min, duration 4–6 h
Tiotropium (LAMA): kinetically selective for M₃ (dissociates very slowly from M₃ vs M₂); once-daily dosing, duration >24 h
Aclidinium, umeclidinium, glycopyrrolate, revefenacin: newer LAMAs, once- or twice-daily
Tiotropium (LAMA): kinetically selective for M₃ (dissociates very slowly from M₃ vs M₂); once-daily dosing, duration >24 h
Aclidinium, umeclidinium, glycopyrrolate, revefenacin: newer LAMAs, once- or twice-daily
Side Effects
- Dry mouth (most common — M₃ blockade of salivary glands)
- Urinary retention (especially in BPH patients)
- Constipation
- Blurred vision / acute angle-closure glaucoma (if drug contacts eyes — especially nebulizer masks)
- Tachycardia (M₂ blockade removes cardiac vagal tone — more with ipratropium)
- Paradoxical bronchospasm (rare)
Katzung's Basic and Clinical Pharmacology, 16th Ed.
3. Inhaled Corticosteroids (ICS)
Mechanism of Action
ICS (fluticasone, budesonide, beclomethasone, mometasone, ciclesonide) are lipophilic molecules that diffuse into cells and bind glucocorticoid receptors (GR) in the cytoplasm. The GR-ligand complex translocates to the nucleus and:
- Trans-activation: induces anti-inflammatory proteins (annexin-1/lipocortin-1, β₂ receptor upregulation, secretory leukocyte protease inhibitor)
- Trans-repression: suppresses NF-κB and AP-1 → ↓ transcription of IL-4, IL-5, IL-13, TNF-α, eotaxin → reduces eosinophilic inflammation, airway hyperresponsiveness, and mucus production
ICS are the cornerstone of asthma controller therapy. In COPD, ICS are used in combination (ICS/LABA) in patients with frequent exacerbations, high blood eosinophils, or asthma-COPD overlap.
Side Effects
Local (oropharyngeal):
- Oropharyngeal candidiasis (use spacer + rinse mouth to minimize)
- Dysphonia (hoarseness — laryngeal myopathy)
- Cough
Systemic (dose-dependent; lower with ICS than oral steroids):
- HPA axis suppression (significant only at high doses)
- Reduced bone mineral density / osteoporosis (long-term high dose)
- Skin thinning, bruising
- Cataracts and glaucoma (long-term)
- Growth suppression in children (small effect; reversible)
- Adrenal insufficiency (rare, high-dose)
4. Methylxanthines (Theophylline, Aminophylline)
Mechanism of Action
Multiple mechanisms (not fully elucidated):
- PDE inhibition → ↑ cAMP and cGMP → bronchodilation (modest at therapeutic concentrations)
- Adenosine receptor antagonism (A₁, A₂) → bronchodilation, stimulation of respiratory drive
- Histone deacetylase (HDAC) activation → anti-inflammatory (enhances steroid sensitivity, especially in COPD)
- Stimulates diaphragm contractility
Side Effects
Narrow therapeutic index (target serum level 5–15 µg/mL):
| Serum Level | Toxicity |
|---|---|
| 15–20 µg/mL | Nausea, vomiting, headache, insomnia |
| 20–30 µg/mL | Sinus tachycardia, arrhythmias |
| >30 µg/mL | Seizures, ventricular arrhythmias (life-threatening) |
Other: GERD exacerbation, diuresis. Many drug interactions (cytochrome P450 — cimetidine, fluoroquinolones, macrolides raise levels; rifampin, phenytoin, smoking lower levels).
5. Leukotriene Modifiers
Montelukast, Zafirlukast (CysLT₁ receptor antagonists)
- Mechanism: Block cysteinyl leukotriene receptors (CysLT₁) on airway smooth muscle, eosinophils, and mast cells → inhibit LTC₄, LTD₄, LTE₄ effects → reduced bronchoconstriction, mucus secretion, and eosinophil recruitment
- Use: Asthma controller (mild persistent); also for aspirin-exacerbated respiratory disease and allergic rhinitis
- Side effects: Generally well tolerated; headache, GI upset. Zafirlukast inhibits CYP2C9 (warfarin interaction). Neuropsychiatric effects (depression, suicidal ideation — FDA black box warning for montelukast)
Zileuton (5-Lipoxygenase inhibitor)
- Mechanism: Inhibits 5-LOX enzyme → blocks synthesis of all leukotrienes (LTB₄ and cysteinyl LTs)
- Side effects: Hepatotoxicity (monitor LFTs), headache, drug interactions (CYP1A2 — warfarin, theophylline levels increased)
6. Mast Cell Stabilizers (Cromolyn Sodium, Nedocromil)
Mechanism of Action
Inhibit degranulation of sensitized mast cells (and eosinophils) upon antigen exposure. Exact mechanism may involve chloride channel blockade and inhibition of sensory nerve activation. Purely prophylactic — no bronchodilator activity.
Side Effects
Very safe (poorly absorbed). Cough and throat irritation with inhalation; rarely bronchospasm. Largely replaced by ICS in clinical practice.
7. Biologics (Severe Asthma)
| Drug | Target | Mechanism | Side Effects |
|---|---|---|---|
| Omalizumab | IgE | Binds free IgE → prevents mast cell/basophil activation | Injection site reactions; rare anaphylaxis |
| Mepolizumab, Reslizumab | IL-5 | Blocks IL-5 → ↓ eosinophil production and survival | Headache, injection reactions; herpes zoster risk |
| Benralizumab | IL-5Rα | Binds IL-5 receptor → direct eosinophil apoptosis (ADCC) | Injection reactions |
| Dupilumab | IL-4Rα | Blocks IL-4 and IL-13 signaling | Injection reactions, conjunctivitis, eosinophilia (transient) |
| Tezepelumab | TSLP | Blocks thymic stromal lymphopoietin (upstream cytokine) | Injection reactions |
8. Phosphodiesterase-4 (PDE4) Inhibitor — Roflumilast
Mechanism
Selective PDE4 inhibitor → ↑ cAMP in immune and structural cells → reduced neutrophil and macrophage activation → anti-inflammatory. Used in severe COPD (FEV₁ <50%, chronic bronchitis phenotype, frequent exacerbations) as add-on to bronchodilators.
Side Effects
- Nausea, diarrhea, abdominal pain (most common, often transient)
- Weight loss
- Headache
- Neuropsychiatric effects (depression, insomnia — use caution in psychiatric history)
- Contraindicated in moderate-to-severe liver impairment
Quick-Reference Summary
COPD Stepwise Approach:
SABA (rescue) → LAMA or LABA (maintenance) → LAMA + LABA
If exacerbations + eosinophilia: add ICS → Triple therapy (ICS + LABA + LAMA)
If chronic bronchitis, FEV1<50%, frequent exacerbations: add roflumilast
Asthma Stepwise Approach (GINA):
Step 1-2: Low-dose ICS + SABA rescue (or as-needed ICS-formoterol)
Step 3: Low-dose ICS + LABA
Step 4: Medium/high ICS + LABA ± LAMA
Step 5: Add biologic (anti-IgE, anti-IL5, anti-IL4R, anti-TSLP)
Sources: Katzung's Basic and Clinical Pharmacology, 16th Ed. · Murray & Nadel's Textbook of Respiratory Medicine · Fishman's Pulmonary Diseases and Disorders
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