MONTELUKAST - A Complete 20-Mark Answer

(RGUHS ENT Pharmacology | Sources: Scott-Brown, Cummings, Harrison's, Katzung, StatPearls + Recent Evidence)

1. INTRODUCTION

• Scott-Brown's Otorhinolaryngology, 9th Ed., Vol. 1, block9, p. 9399
• Cummings Otolaryngology Head and Neck Surgery, block7, p. 3129

2. LEUKOTRIENE PATHWAY - MECHANISM DIAGRAM

3. MECHANISM OF ACTION (FLOW CHART)

ALLERGEN EXPOSURE
       ↓
Mast cell / eosinophil / basophil activation
       ↓
Cell-membrane phospholipids
       ↓ [Phospholipase A2]
Arachidonic acid released
       ↓ [5-Lipoxygenase + FLAP]
5-HPETE (5-hydroperoxyeicosatetraenoic acid)
       ↓
LTA4 (Leukotriene A4)
    ↙         ↘
[LTC4 synthase]   [LTA4 hydrolase]
   LTC4            LTB4
    ↓           (Neutrophil chemotaxis)
   LTD4 (most potent)
    ↓
   LTE4
    ↓
CysLT1 RECEPTOR binding
    ↓
Effects:
• Bronchoconstriction
• ↑ Vascular permeability (nasal congestion/edema)
• Mucus hypersecretion
• Eosinophil recruitment
• Nasal mucosal inflammation
    ↓
⛔ MONTELUKAST BLOCKS CysLT1 RECEPTOR
→ Prevents all above effects

• Montelukast binds the CysLT1 receptor with high affinity and without agonist activity (pure competitive antagonist).
• It does not block the CysLT2 receptor.
• The binding affinity for the receptor is approximately 8.2 nM.
• It also inhibits airway edema, smooth muscle contraction, and impaired cellular activity.

4. PHARMACOKINETICS

• Rapidly absorbed after oral dosing
• Food does not affect absorption significantly (can be taken without regard to food)
• The chewable tablet for children contains phenylalanine - caution in phenylketonuria
• Onset of therapeutic effect: within hours for acute relief; maximum chronic benefit within 1 month

5. FDA-APPROVED INDICATIONS (ENT & Respiratory)

┌─────────────────────────────────────────────────────────────┐
│                   MONTELUKAST INDICATIONS                    │
├─────────────────────────────────────────────────────────────┤
│  1. Chronic Asthma prophylaxis (adults + children ≥1 yr)    │
│  2. Seasonal Allergic Rhinitis (adults + children ≥2 yr)    │
│  3. Perennial Allergic Rhinitis (adults + children ≥6 mo)   │
│  4. Exercise-Induced Bronchoconstriction (EIB) prevention   │
├─────────────────────────────────────────────────────────────┤
│              OFF-LABEL / EMERGING USES IN ENT               │
├─────────────────────────────────────────────────────────────┤
│  5. Chronic Rhinosinusitis with Nasal Polyps (adjunct)      │
│  6. AFRS (Allergic Fungal Rhinosinusitis) - case reports    │
│  7. Aspirin-Exacerbated Respiratory Disease (AERD)          │
│  8. Otitis media with effusion (OME) - limited evidence     │
└─────────────────────────────────────────────────────────────┘

6. DOSING

• For EIB prevention: take at least 2 hours before exercise; do not take an additional dose within 24 hours
• No dose adjustment needed for hepatic/renal impairment (mild-moderate)

7. ROLE IN ENT CONDITIONS

7.1 Allergic Rhinitis (AR)

• Leukotrienes are generated in AR; montelukast is approved for both seasonal and perennial AR
• Equal efficacy to antihistamines (e.g., loratadine) for nasal symptom control
• Less effective than intranasal corticosteroids (INCS) - INCS remain the gold standard
• The 2018 AAO-HNS and International Consensus Statement recommend against routine monotherapy with montelukast for AR due to decreased relative efficacy and increased cost
• Most beneficial in patients with concurrent asthma + AR ("one airway, one disease" concept)

Mild Intermittent AR → Oral antihistamine / INCS
       ↓
Moderate-Severe / Persistent AR → INCS (first-line)
       ↓
Inadequate control / Concurrent Asthma → ADD Montelukast
       ↓
Further Escalation → Allergen Immunotherapy / Biologics

7.2 Chronic Rhinosinusitis with Nasal Polyps (CRSwNP)

• Montelukast studied as adjunct to steroid treatment in CRSwNP with asthma
• One positive single-blinded placebo-controlled cross-over study shows benefit over placebo
• Three other randomized trials negative for change in polyp scores
• Some benefits seen for sneezing and facial pain in subset studies
• Most benefit in patients with associated nasal allergy
• Mechanism: possibly through control of concomitant AR rather than direct polyp effect

7.3 Aspirin-Exacerbated Respiratory Disease (AERD / Samter's Triad)

Aspirin / NSAIDs block cyclooxygenase pathway
       ↓
Shunting of arachidonic acid to 5-lipoxygenase pathway
       ↓
Massive overproduction of cysteinyl leukotrienes
       ↓
Nasal polyps + asthma + bronchospasm
       ↓
MONTELUKAST = PARTICULARLY EFFECTIVE in this subgroup

7.4 Allergic Fungal Rhinosinusitis (AFRS)

• To date, no evidence that montelukast has a role in standard treatment of AFRS
• Only one case study reported benefit: 10 mg oral montelukast in a patient with recalcitrant AFRS with recurrent symptoms following three previous sinus surgeries

7.5 Otitis Media with Effusion (OME)

• Emerging data suggest leukotrienes play a role in middle ear inflammation
• Some studies show modest benefit of LTRA in OME, but evidence is insufficient for routine use
• Referenced in Zakir Hussain and Dhingra as an area of ongoing investigation

8. COMPARISON WITH OTHER DRUGS IN AR

┌──────────────────┬──────────────┬─────────────────┬────────────────┐
│ Drug Class       │ Route        │ Efficacy in AR  │ Best For       │
├──────────────────┼──────────────┼─────────────────┼────────────────┤
│ INCS             │ Intranasal   │ BEST (1st line) │ Congestion,    │
│ (fluticasone)    │              │                 │ all symptoms   │
├──────────────────┼──────────────┼─────────────────┼────────────────┤
│ Antihistamines   │ Oral/topical │ Good            │ Sneezing,      │
│ (cetirizine)     │              │                 │ itching,       │
│                  │              │                 │ rhinorrhoea    │
├──────────────────┼──────────────┼─────────────────┼────────────────┤
│ MONTELUKAST      │ Oral         │ Equal to        │ Concurrent     │
│                  │              │ antihistamine   │ asthma + AR;   │
│                  │              │ < INCS          │ AERD; children │
├──────────────────┼──────────────┼─────────────────┼────────────────┤
│ Zileuton         │ Oral         │ Slightly >      │ Refractory     │
│ (5-LO inhibitor) │              │ montelukast     │ asthma (liver  │
│                  │              │                 │ monitoring)    │
└──────────────────┴──────────────┴─────────────────┴────────────────┘

9. ADVERSE EFFECTS

Common (>1%):

• Headache (most common)
• Abdominal pain, nausea, diarrhea
• Nasopharyngitis, upper respiratory infection
• Dizziness, fatigue

⚠️ BOXED WARNING (FDA 2020) - Neuropsychiatric Events:

NEUROPSYCHIATRIC ADVERSE EFFECTS OF MONTELUKAST:
┌──────────────────────────────────────────────────┐
│ • Agitation, aggression                          │
│ • Anxiety, depression                            │
│ • Sleep disturbances (insomnia, somnambulism,   │
│   dream abnormalities, nightmares)               │
│ • Attention/memory impairment                    │
│ • Seizures, paraesthesia                         │
│ • Suicidal ideation and behaviour ← MOST SERIOUS │
└──────────────────────────────────────────────────┘
Reported in: Adults, teenagers, AND children
FDA issued initial warning: 2008
FDA upgraded to BLACK BOX WARNING: March 2020

• The FDA boxed warning states these risks outweigh the benefits in AR where alternative agents are available
• Risk is lower in asthma where benefits are clearer

Rare but Serious:

• Churg-Strauss Syndrome (eosinophilic granulomatosis with polyangiitis): systemic eosinophilia + vasculitis, often with dose reduction/withdrawal of corticosteroids - causal relationship not fully established
• Hepatic transaminase elevation (rare)
• Hypersensitivity reactions (angioedema, urticaria)

10. DRUG INTERACTIONS

11. CONTRAINDICATIONS

• Known hypersensitivity to montelukast or any component
• Phenylketonuria (chewable tablet contains phenylalanine - relative contraindication)
• Not indicated for acute bronchospasm (no rapid bronchodilator effect)
• NOT a substitute for rescue beta-agonist in acute asthma

12. SPECIAL POPULATIONS

13. ADVANTAGES OF MONTELUKAST IN ENT/PAEDIATRIC PRACTICE

✓ ORAL administration (unlike INCS - good compliance)
✓ Once-daily dosing
✓ No rhinitis medicamentosa
✓ No systemic steroid side effects
✓ Effective for BOTH nasal AND lower airway symptoms
✓ Addresses "unified airway" - AR + asthma together
✓ Safe in children from 6 months of age
✓ No tachyphylaxis (unlike LABAs for EIB)
✓ Particularly effective in AERD

14. RECENT ADVANCES (2021-2026)

14.1 FDA Boxed Warning Impact (2026)

14.2 Montelukast + Levocetirizine Combination (2026)

• Combination therapy (montelukast + levocetirizine) gave superior symptom control vs monotherapy
• Greater improvement in daytime symptoms (SMD -0.42), rhinorrhoea (SMD -0.69), nasal congestion (SMD -0.64)
• TEAE rates were similar across groups (OR 1.05) - no added harm
• Supports combination use in patients with persistent or poorly controlled AR

14.3 Paediatric Meta-Analysis (2023)

• Montelukast effective vs placebo in controlling asthma symptoms (SMD 0.90)
• Inhaled corticosteroids superior for night-time symptom control (SMD -0.23)
• Quality of life difference was not statistically significant

14.4 Neuropsychiatric Risk in Children (2025)

14.5 Biomarker-Guided Therapy

• Start maintenance montelukast when EDN ≥ 53 ng/mL (1 SD above normal)
• Discontinue when EDN falls to < 45 ng/mL
• This is the first validated biomarker approach for LTRA therapy monitoring

14.6 Montelukast in OME

15. SUMMARY FLOW CHART - PLACE OF MONTELUKAST IN AR MANAGEMENT

Patient presents with Allergic Rhinitis
              ↓
         Severity Assessment
        ↙               ↘
Mild Intermittent    Moderate-Severe / Persistent
    ↓                        ↓
Oral antihistamine      INTRANASAL CORTICOSTEROID
   OR INCS              (FIRST-LINE TREATMENT)
    ↓                        ↓
Adequate control?    Adequate control?
    ↓ Yes                ↓ No
  Continue         Add oral antihistamine
                          ↓
                   Still inadequate?
                          ↓
             ADD MONTELUKAST
             (especially if concurrent asthma,
              AERD, or in children)
                          ↓
                  Still not controlled?
                          ↓
              Allergen Immunotherapy
              + Consider Biologics
              (Dupilumab, Omalizumab)

16. IMPORTANT POINTS FOR RGUHS EXAM

1. Class: Selective CysLT1 receptor antagonist (NOT a bronchodilator, NOT an antihistamine)
2. Key comparison: Less effective than INCS but more convenient (oral); equal to antihistamines
3. Best clinical scenario: AR + concurrent asthma ("unified airway disease")
4. AERD is the best indication - massive leukotriene overproduction
5. Black box warning: Neuropsychiatric effects including suicidal ideation (2020)
6. Zileuton vs Montelukast: Zileuton inhibits 5-lipoxygenase (reduces synthesis); montelukast blocks the receptor
7. NOT for acute attack: Has no immediate bronchodilator effect
8. Churg-Strauss: Rare but serious - association described especially with corticosteroid dose reduction
9. Paediatric use: Drug of choice when ICS growth suppression is a concern
10. Dose: 10 mg OD (adults), 5 mg OD (6-14 yr), 4 mg OD (2-5 yr)

REFERENCES

Note for RGUHS students: This question frequently appears as "Write a note on leukotriene receptor antagonists in ENT" or "Discuss montelukast - mechanism, uses, adverse effects." For 20 marks, include: definition + class, mechanism (with pathway), pharmacokinetics, all ENT indications, dosing, adverse effects (especially black box), drug interactions, comparison table with INCS and antihistamines, and 2-3 recent advances. The leukotriene biosynthesis diagram above is the single most important diagram for this topic.