Drugs Used in Treatment of Bronchial Asthma

Mechanism Overview

Classification of Antiasthmatic Drugs

A. Bronchodilators (Relievers)

1. Beta-2 adrenergic agonists
   • Short-acting (SABA): Salbutamol (albuterol), terbutaline, fenoterol
   • Long-acting (LABA): Salmeterol, formoterol
2. Methylxanthines: Theophylline, aminophylline, doxofylline
3. Anticholinergics (Antimuscarinics): Ipratropium bromide (SAMA), tiotropium (LAMA)

B. Anti-inflammatory / Controllers

1. Corticosteroids
   • Inhaled (ICS): Beclomethasone, budesonide, fluticasone, mometasone
   • Systemic: Prednisolone, methylprednisolone (for acute exacerbations)
2. Leukotriene Modifiers
   • 5-LOX inhibitor: Zileuton
   • Cysteinyl LT-receptor antagonists (LTRAs): Montelukast, zafirlukast
3. Mast cell stabilizers: Cromolyn sodium (sodium cromoglycate), nedocromil
4. Biologics / Monoclonal antibodies: Omalizumab (anti-IgE), mepolizumab, benralizumab (anti-IL-5)

1. Beta-2 Adrenergic Agonists

Mechanism

Pharmacokinetics

• Inhaled route preferred - greatest local effect with least systemic toxicity
• Optimal aerosol particle size: 2-5 µm
• 80-90% of inhaled dose is deposited in oropharynx
• Salbutamol: partially metabolized to inactive sulfate conjugate; excreted in urine
• Salmeterol: highly lipophilic, binds exosite on beta-2 receptor - explains long duration

Adverse Effects

• Tachycardia and palpitations (beta-1 stimulation, especially non-selective agents)
• Skeletal muscle tremor (fine tremor of hands - most common)
• Hypokalemia (K+ enters cells via Na/K-ATPase stimulation) - can cause arrhythmias
• Nervousness, headache, dizziness
• With LABAs alone (without ICS): increased risk of asthma-related death (black box warning - never use LABA as monotherapy in asthma)

Therapeutic Uses

• SABAs: First-line reliever for acute bronchoconstriction, exercise-induced bronchospasm
• LABAs: Added to ICS for moderate-to-severe persistent asthma (never alone)
• Terbutaline SC: acute severe asthma when inhaled route not possible
• Formoterol: also used as reliever due to fast onset (unlike salmeterol)

2. Methylxanthines (Theophylline)

Mechanism

1. PDE inhibition → prevents cAMP breakdown → bronchodilation (main mechanism at therapeutic levels)
2. Adenosine receptor antagonism → blocks bronchoconstriction
3. Anti-inflammatory effects (at low concentrations)
4. Increases diaphragm contractility - useful in COPD
5. Mild CNS stimulation

Pharmacokinetics

• Given orally (slow-release tablets preferred) or IV as aminophylline
• Aminophylline = theophylline + ethylenediamine (80% theophylline, more water-soluble)
• Therapeutic serum level: 10-20 mg/L (narrow therapeutic index)
• Toxic level: >20 mg/L
• Hepatic metabolism via CYP1A2 - extensive drug interactions
• Half-life: 8-9 hrs in adults (varies widely)
• Half-life is shortened (t½ decreases) by: smoking, rifampicin, phenytoin, carbamazepine
• Half-life is prolonged (t½ increases) by: erythromycin, ciprofloxacin, cimetidine, heart failure, liver disease, old age

Adverse Effects (dose-dependent, narrow TI)

• Mild (10-20 mg/L): Nausea, vomiting, anorexia, headache, insomnia, restlessness
• Moderate (>20 mg/L): Tachycardia, arrhythmias, hypokalemia, tremor
• Severe toxicity (>40 mg/L): Seizures, ventricular arrhythmias, death
• GI: stimulates gastric acid secretion (avoid in peptic ulcer disease)

Therapeutic Uses

• Oral slow-release: chronic asthma (now largely replaced by ICS)
• IV aminophylline: severe acute asthma / status asthmaticus (as add-on)
• COPD with frequent exacerbations
• Apnea of prematurity (neonates - caffeine preferred)

3. Anticholinergics (Antimuscarinics)

Mechanism

Pharmacokinetics

• Ipratropium bromide: Inhaled (MDI/nebulizer), onset 15-30 min, duration 4-6 hrs; quaternary ammonium compound - poorly absorbed systemically, minimal CNS effects
• Tiotropium: Inhaled (DPI), long-acting (once daily, 24 hrs), primarily used in COPD

Adverse Effects

• Dry mouth (most common)
• Urinary retention (caution in BPH)
• Constipation
• Blurred vision (if accidentally sprayed in eyes)
• Tachycardia (less than atropine because poorly absorbed)
• Does NOT cause the systemic anticholinergic effects of atropine (crosses blood-brain barrier poorly)

Therapeutic Uses

• COPD: Drug of choice (tiotropium preferred)
• Asthma: Alternative bronchodilator; particularly useful in:
  • Patients with beta-blocker-induced bronchospasm
  • Psychogenic asthma
  • Nocturnal asthma
  • Acute severe asthma (combined with salbutamol in nebulization)
• Not first-line for asthma (beta-2 agonists preferred)

4. Corticosteroids

Mechanism

• Inhibit phospholipase A2 → reduce arachidonic acid release → decrease prostaglandins AND leukotrienes
• Reduce inflammatory cell infiltration (eosinophils, macrophages, T lymphocytes)
• Reverse mucosal edema, decrease capillary permeability
• Inhibit leukotriene release
• After months of regular use: reduce airway hyperresponsiveness

Pharmacokinetics (ICS)

• Inhaled route: 80-90% deposited in oropharynx (swallowed) → first-pass hepatic inactivation reduces systemic absorption
• Spacer device reduces oropharyngeal deposition
• Systemic steroids (prednisolone): well-absorbed orally, hepatically metabolized

Adverse Effects

• Oropharyngeal candidiasis (thrush) - prevented by rinsing mouth after use
• Dysphonia (hoarseness) - due to vocal cord myopathy
• Cough, irritation

• Adrenal suppression
• Growth retardation in children (small effect)
• Osteoporosis
• Cataracts, glaucoma

• Cushing syndrome, osteoporosis, hypertension, hyperglycemia
• Peptic ulcer, immunosuppression, myopathy
• HPA axis suppression

Therapeutic Uses

• ICS: Foundation of controller therapy in all grades of persistent asthma
• Oral prednisolone: acute severe asthma (short course / "burst")
• IV methylprednisolone: status asthmaticus
• Key principle: ICS + LABA combination (e.g., fluticasone-salmeterol, budesonide-formoterol) for moderate-severe persistent asthma

5. Leukotriene Modifiers

Mechanism

• Zileuton: Inhibits 5-lipoxygenase → prevents formation of ALL leukotrienes (LTB4 + cysteinyl LTs: LTC4, LTD4, LTE4)
• Montelukast, zafirlukast: Selective CysLT1 receptor antagonists → block effects of cysteinyl leukotrienes (bronchoconstriction, edema, mucus secretion)

Pharmacokinetics

• All are orally active, highly protein-bound
• Extensive hepatic metabolism
• Zileuton + metabolites: excreted in urine
• Montelukast, zafirlukast + metabolites: biliary excretion
• Food impairs absorption of zafirlukast (take on empty stomach)

Adverse Effects

• Montelukast: Headache, GI upset; black box warning - serious neuropsychiatric effects (agitation, depression, suicidal ideation, sleep disturbances)
• Zafirlukast, zileuton: Elevated liver enzymes (monitor LFTs), headache, dyspepsia
• Zafirlukast inhibits CYP2C9, 3A4 (drug interactions - warfarin levels increase)
• Zileuton inhibits CYP1A2
• Rare: Eosinophilic granulomatosis with polyangiitis (EGPA) / Churg-Strauss syndrome (especially when oral steroids tapered)

Therapeutic Uses

• Mild persistent asthma (alternative to ICS or add-on)
• Aspirin-exacerbated respiratory disease (AERD) - particularly effective
• Exercise-induced bronchospasm - prevention
• Allergic rhinitis (montelukast)
• Not for acute attacks (no bronchodilator effect)

6. Mast Cell Stabilizers

Mechanism

Pharmacokinetics

• Cromolyn sodium: Inhaled (nebulizer), poor oral bioavailability (<1%), excreted unchanged in urine and bile
• Short duration - requires 3-4 times daily dosing
• Nedocromil: inhaled, 4 times daily

Adverse Effects

• Very safe - minimal adverse effects
• Cough, throat irritation, unpleasant taste (cromolyn)
• Not a bronchodilator - useless in acute attack

Therapeutic Uses

• Prophylaxis only - not for acute attacks
• Alternative therapy for mild persistent asthma (especially children)
• Prevention of exercise-induced and allergen-induced bronchospasm (taken 15-20 min before)
• Allergic rhinitis (nasal spray), mastocytosis (oral cromolyn)

7. Biologics (Monoclonal Antibodies)

• Given SC every 2-4 weeks
• Reserved for severe uncontrolled asthma despite maximum ICS + LABA therapy
• Omalizumab dose based on IgE level and body weight

Step-wise Treatment (GINA Guidelines Summary)

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