Bronchial Asthma - Pharmacology Viva Rapid Revision

1. Definition (Quick Opener)

2. Pathophysiology (Know for Mechanism Questions)

• Early phase (0-30 min): Allergen activates mast cells via IgE → releases histamine, leukotrienes (LTC4, LTD4, LTE4), and prostaglandins → immediate bronchoconstriction
• Late phase (4-8 hrs): Eosinophil and T-lymphocyte infiltration → sustained inflammation, mucus, airway remodeling
• Key mediators: Histamine, LTs, PGD2, PAF, TNF-α, IL-4, IL-5, IL-13
• cAMP ↑ → bronchodilation; cGMP ↑ → bronchoconstriction

3. Drug Classification

4. Key Drug Mechanisms (Most Asked in Viva)

Beta-2 Agonists

• MOA: Bind β2 receptors on airway smooth muscle → activate adenylyl cyclase → ↑cAMP → bronchodilation. Also inhibit mast cell mediator release.
• SABA onset: 5 min; duration: 4-6 hrs
• SABA (Salbutamol): Drug of choice for acute attack; metered dose inhaler (MDI) preferred
• LABA (Salmeterol): Onset 15-30 min; duration 12 hrs. Long lipophilic side chain anchors it in membrane.
• Formoterol: LABA with fast onset (like SABA) - can be used for both relief and maintenance (SMART regimen with budesonide)
• SE: Tachycardia (β1), tremor, hypokalemia (K+ shift into cells), tolerance with overuse

Corticosteroids (ICS)

• MOA: Bind glucocorticoid receptor → nuclear translocation → inhibit transcription of inflammatory cytokines (IL-4, IL-5, IL-13, TNF-α). Reduce eosinophil and mast cell infiltration. Reduce bronchial hyperreactivity. Do NOT directly relax smooth muscle.
• ICS drugs: Beclomethasone, budesonide, fluticasone, mometasone, ciclesonide
• SE of ICS: Oral candidiasis, dysphonia (hoarseness) - prevented by rinsing mouth after use
• Systemic steroids (IV hydrocortisone, oral prednisolone): Used in severe acute attacks and status asthmaticus

Theophylline

• MOA: PDE inhibitor → prevents cAMP breakdown → bronchodilation. Also adenosine receptor antagonist (blocks adenosine-induced bronchoconstriction).
• Narrow therapeutic index: 10-20 mcg/mL (therapeutic); >20 mcg/mL toxic
• SE: Nausea/vomiting (early), arrhythmias, seizures (toxic levels)
• Drug interactions: Cimetidine, erythromycin, ciprofloxacin INCREASE levels (inhibit CYP1A2). Smoking, rifampicin DECREASE levels.
• Aminophylline: Water-soluble theophylline salt; given IV in acute severe asthma

Anticholinergics

• MOA: Block M3 muscarinic receptors on bronchial smooth muscle → inhibit acetylcholine-induced bronchoconstriction
• Ipratropium bromide (SAMA): Quaternary ammonium - poor systemic absorption, no CNS effects. Used as add-on in acute severe asthma (combined with salbutamol nebulization)
• Tiotropium (LAMA): 24-hr duration; now approved for asthma maintenance (add-on to ICS). Dissociates rapidly from M2 receptors (preserving ACh feedback inhibition).
• SE: Dry mouth, urinary retention (rare), worsening glaucoma if sprayed in eye

Leukotriene Modifiers

• Montelukast, zafirlukast: CysLT1 receptor blockers → block LTC4, LTD4, LTE4 effects
• Zileuton: 5-lipoxygenase inhibitor → blocks ALL leukotriene synthesis (including LTB4)
• Uses: Mild persistent asthma, aspirin-sensitive asthma (ASA exacerbates via 5-LOX shunting), exercise-induced asthma, allergic rhinitis with asthma
• Montelukast SE: Neuropsychiatric effects (nightmares, depression, suicidal ideation - black box warning)

Cromolyn Sodium / Nedocromil

• MOA: Stabilize mast cell membranes → prevent degranulation → no mediator release. Block Cl- channels. Also inhibit sensory nerve activation.
• Only prophylactic - no bronchodilator effect, useless in acute attack
• Best indication: Exercise-induced asthma (inhaled before exercise), allergen-induced asthma
• SE: Very safe; minor throat irritation

Omalizumab (Anti-IgE)

• MOA: Monoclonal antibody that binds free serum IgE → prevents IgE binding to mast cell FcεRI receptors → blocks allergic cascade
• Use: Moderate-to-severe allergic asthma not controlled by ICS+LABA
• Given: SC injection every 2-4 weeks
• SE: Injection site reactions; rare anaphylaxis (observe for 30-60 min after each dose)

5. Stepwise Management (GINA-based)

6. Status Asthmaticus Management

1. Oxygen - maintain SpO2 >94%
2. Nebulized salbutamol (2.5-5 mg) + ipratropium (0.5 mg) - repeat every 20 min x3
3. IV/oral corticosteroids - hydrocortisone 100-200 mg IV or prednisolone 40-60 mg oral
4. IV aminophylline - if no response (load 5 mg/kg over 20 min, then infusion)
5. IV magnesium sulfate (2 g IV) - bronchodilation via Ca2+ channel blockade
6. Heliox, intubation - in life-threatening cases

7. High-Yield Viva Points

8. Quick Mechanism Diagram (Memorize)

Allergen → IgE on mast cells → Mast cell activation
       ↓
Histamine, LTs, PGD2 → Bronchoconstriction + inflammation
       ↓
β2 agonists → ↑cAMP → Smooth muscle relaxation (RELIEF)
ICS → ↓Cytokines, ↓eosinophils (CONTROL)
Anticholinergics → Block M3 → ↓ACh bronchoconstriction
Montelukast → Block CysLT1 → ↓LT-mediated bronchoconstriction
Theophylline → ↓PDE → ↑cAMP → Bronchodilation

Theophylline - Complete Explanation

What is it?

Mechanism of Action (3 Proposed Mechanisms)

1. PDE (Phosphodiesterase) Inhibition - Primary MOA

• Normally, cAMP is broken down by the enzyme phosphodiesterase (PDE)
• Theophylline inhibits PDE → cAMP is NOT broken down → intracellular cAMP accumulates
• High cAMP → smooth muscle relaxation → bronchodilation
• Specifically: PDE3 inhibition relaxes airway smooth muscle; PDE4 inhibition reduces cytokine release (anti-inflammatory effect at lower doses)

Theophylline → inhibits PDE → ↓breakdown of cAMP → ↑cAMP → Bronchodilation

2. Adenosine Receptor Antagonism - Secondary MOA

• Adenosine (a local mediator) normally acts on airway smooth muscle → causes bronchoconstriction + histamine release from mast cells
• Theophylline blocks adenosine receptors → prevents adenosine-induced bronchoconstriction
• Note: Some xanthines without adenosine antagonism (e.g., enprofylline) still cause bronchodilation, so this is NOT the sole mechanism

3. Histone Deacetylase (HDAC) Enhancement - Newer MOA

• Inflammatory gene transcription requires acetylation of histones
• Low-dose theophylline enhances the action of HDAC → reduces inflammatory gene transcription
• This is the same pathway by which corticosteroids work - so low-dose theophylline actually potentiates ICS effects
• This explains why theophylline has anti-inflammatory activity at sub-bronchodilator doses

Pharmacokinetics (Very Important for Viva)

Therapeutic Drug Monitoring (Narrow Therapeutic Index)

Drug Interactions (Very Commonly Asked)

Drugs that INCREASE theophylline levels (toxic):

Drugs that DECREASE theophylline levels (sub-therapeutic):

Viva tip: Smokers need higher doses of theophylline. When they quit smoking, levels rise - monitor carefully.

Pharmacological Effects Across Organ Systems

Clinical Uses

1. Acute severe asthma / Status asthmaticus: IV aminophylline (loading dose 5-6 mg/kg over 20-30 min, then maintenance infusion of 0.5-0.9 mg/kg/hr). Use only if patient is not already on oral theophylline.
2. Chronic asthma: Oral sustained-release theophylline as add-on to ICS (Step 3-4). Less popular now due to narrow TI.
3. COPD: Add-on for patients with persistent symptoms.
4. Apnea of prematurity: Methylxanthines (theophylline/caffeine) stimulate respiratory center - caffeine preferred now.

Toxicity and Management

• Early: Nausea, vomiting (most common first symptom), headache, tremor, insomnia
• Intermediate: Tachycardia, hypokalemia (due to β2-adrenergic activation), hyperglycemia
• Severe: Ventricular arrhythmias, seizures (resistant to regular anticonvulsants), hypotension

1. Activated charcoal - repeated doses (theophylline undergoes enterohepatic circulation, so repeat doses are effective)
2. Whole bowel irrigation - especially for sustained-release formulations (toxicity can be delayed for hours)
3. Propranolol / esmolol (β-blockers) - specific antidote for β2-mediated tachycardia and hypotension
4. Benzodiazepines - for seizures
5. Hemodialysis - if serum level >100 mcg/mL or intractable seizures

Roflumilast - Selective PDE4 Inhibitor (Bonus)

• Selective PDE4 inhibitor developed to reduce theophylline's toxicity
• FDA approved for COPD (reduces exacerbations), NOT asthma
• SE: Nausea, headache, diarrhea (limits use)

Quick Recall Table

Histone Deacetylase (HDAC) in Asthma - Deep Explanation

Step 1: Start with the Basics - What is a Histone?

Step 2: Acetylation vs Deacetylation

• Acetylation = gene ON (chromatin open, euchromatin)
• Deacetylation = gene OFF (chromatin closed, heterochromatin)

Step 3: What Happens in Asthma (The Inflammatory Process)

Allergen/IL-1β/TNF-α
        ↓
Activates IKKβ (IκB Kinase beta)
        ↓
Activates NF-κB (Nuclear Factor kappa B) - the "master inflammatory switch"
        ↓
NF-κB moves into nucleus
        ↓
Recruits coactivators (like CBP - CREB Binding Protein)
CBP has HAT (Histone AcetylTransferase) activity
        ↓
HAT adds acetyl groups to histones
        ↓
Chromatin OPENS → Inflammatory genes transcribed
        ↓
IL-4, IL-5, IL-13, TNF-α, GM-CSF produced
        ↓
Eosinophil infiltration, bronchoconstriction, mucus, airway remodeling

Step 4: How Corticosteroids Switch Off Inflammation (via HDAC2)

Corticosteroid enters cell
        ↓
Binds Glucocorticoid Receptor (GR) in cytoplasm
        ↓
GR-steroid complex moves into nucleus
        ↓
Does TWO things simultaneously:

1. Directly inhibits HAT activity (prevents further acetylation)
2. Recruits HDAC2 to the site of already-acetylated inflammatory genes
        ↓
HDAC2 removes acetyl groups from histones
        ↓
Chromatin CLOSES → Inflammatory genes switched OFF
        ↓
↓ IL-4, IL-5, IL-13, TNF-α, GM-CSF etc.
        ↓
Anti-inflammatory effect in asthma

Step 5: Where Theophylline Fits In - The Key Pharmacology Point

Low-dose theophylline
        ↓
Directly activates HDAC2 (nuclear enzyme)
        ↓
HDAC2 deacetylates histones at inflammatory gene sites
        ↓
Inflammatory genes switched OFF
        ↓
Anti-inflammatory effect (independent of PDE inhibition)

Why this makes theophylline + ICS a powerful combination:

Step 6: The COPD/Steroid Resistance Connection

• Corticosteroids cannot recruit a functional HDAC2
• Inflammatory genes stay ON
• Patient becomes steroid-resistant

Step 7: Clinical Implication Summary

The Full Pathway in One Picture

INFLAMMATION PATH (Bad):
NF-κB → HAT → Histone ACETYLATION → Genes ON → Cytokines → Asthma

CORTICOSTEROID PATH (Good):
ICS → Glucocorticoid Receptor → Recruits HDAC2 → Histone DEACETYLATION → Genes OFF

THEOPHYLLINE ENHANCEMENT:
Low-dose theophylline → Activates HDAC2 directly → Potentiates ICS effect

One-Line Summary for Viva

"Inflammatory stimuli (via NF-κB) activate HAT, which acetylates histones and switches ON inflammatory genes. Corticosteroids recruit HDAC2 to deacetylate these histones and switch the genes OFF. Low-dose theophylline directly activates HDAC2, enhancing the steroid effect - this explains its anti-inflammatory action at sub-bronchodilator plasma levels."