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Wednesday, August 6, 2025

Mast cell stabilizers


Definition

Mast cell stabilizers are a class of pharmacologic agents that prevent the release of pro-inflammatory mediators—primarily histamine, leukotrienes, prostaglandins, cytokines, and other vasoactive substances—from sensitized mast cells. By inhibiting mast cell degranulation, these drugs reduce the initiation of IgE-mediated hypersensitivity reactions, especially those related to allergic rhinitis, conjunctivitis, asthma, and systemic mastocytosis.

Unlike antihistamines, which block histamine after it is released, mast cell stabilizers prevent its release altogether. Their onset is slow, so they are used prophylactically rather than for immediate symptom relief.

Mechanism of Action

Mast cells are immune cells found abundantly in the skin, mucosa, lungs, and gastrointestinal tract. When activated (usually via IgE cross-linking), they degranulate, releasing potent inflammatory mediators.

Mast cell stabilizers inhibit this process by:

  1. Blocking calcium influx into mast cells

    • Prevents degranulation, which is calcium-dependent

  2. Inhibiting Cl⁻ channels

    • Stabilizes mast cell membranes by altering transmembrane potential

  3. Preventing activation of intracellular signaling pathways

    • Interferes with protein kinase C and other pathways involved in mast cell activation

  4. Downregulating inflammatory gene transcription

    • Indirect anti-inflammatory properties in chronic allergic conditions

The result is reduced mediator release, leading to suppression of allergic cascade initiation.

Therapeutic Classes and Examples

Mast cell stabilizers may be administered via different routes depending on the indication:

Formulation RouteDrug ExamplesPrimary Indications
InhalationCromolyn sodium (Intal), Nedocromil sodiumAsthma prophylaxis
OphthalmicLodoxamide, Cromolyn sodium, NedocromilAllergic conjunctivitis, vernal keratoconjunctivitis
NasalCromolyn sodium nasal sprayAllergic rhinitis
OralCromolyn sodium (Gastrocrom)Mastocytosis, food allergies, systemic allergic disease
CutaneousPemirolast (topical), Ketotifen (combined action)Contact dermatitis (experimental)



Key Drug Profiles

1. Cromolyn Sodium (Sodium Cromoglicate)

  • Oldest and most studied mast cell stabilizer

  • Mechanism: Prevents calcium influx into mast cells, stabilizing their membranes

  • Uses:

    • Asthma (inhaled)

    • Allergic rhinitis (nasal spray)

    • Conjunctivitis (eye drops)

    • Mastocytosis (oral)

  • Formulations:

    • Inhalation (Intal): Discontinued in many markets but available as generic

    • Oral solution (Gastrocrom): 100 mg/5 mL

    • Nasal spray: 4% w/v

    • Eye drops: 2% solution

  • Dosing:

    • Asthma: 20 mg (via nebulizer) QID

    • Allergic rhinitis: 1 spray each nostril 3–6 times/day

    • Oral: 200 mg QID, 30 minutes before meals and bedtime

2. Nedocromil Sodium

  • Newer mast cell stabilizer

  • Mechanism: Same as cromolyn but also inhibits eosinophil activation

  • Indications:

    • Mild to moderate asthma (inhaled)

    • Allergic eye conditions (as eye drops)

  • Formulations:

    • 2% ophthalmic solution

    • Inhalation (Tilade): Discontinued in many regions

3. Lodoxamide Tromethamine

  • More potent than cromolyn in ocular allergy

  • Indications: Vernal keratoconjunctivitis, seasonal allergic conjunctivitis

  • Formulation: 0.1% ophthalmic solution

  • Dosing: 1–2 drops in affected eye(s) QID

4. Ketotifen Fumarate

  • Not a pure mast cell stabilizer – dual-action drug

  • Blocks H1 receptors + stabilizes mast cells

  • Indications: Allergic conjunctivitis (topical), asthma prophylaxis (oral, international use)

5. Pemirolast Potassium

  • Dual-action (mast cell stabilizer + anti-allergic)

  • Ophthalmic solution for allergic conjunctivitis

  • Withdrawn from several markets due to availability of newer agents

Clinical Indications

Mast cell stabilizers are effective in a wide range of allergic and hypersensitivity disorders, including:

  1. Bronchial Asthma (non-acute)

    • Long-term prophylaxis in mild persistent asthma

    • Used in children, or as steroid-sparing agents

  2. Allergic Rhinitis

    • Effective for seasonal and perennial rhinitis

    • Nasal sprays reduce sneezing, nasal congestion, rhinorrhea

  3. Allergic Conjunctivitis

    • Useful in vernal keratoconjunctivitis, seasonal, and giant papillary conjunctivitis

  4. Systemic Mastocytosis

    • Oral cromolyn reduces gastrointestinal symptoms, flushing, and pruritus

  5. Food Allergy

    • Prevention of food-induced allergic reactions in diagnosed cases (non-anaphylactic)

    • Oral cromolyn may reduce symptoms but does not replace allergen avoidance

  6. Eosinophilic Gastroenteritis / Colitis

    • Off-label use in children and adults

  7. Dermatologic Hypersensitivity

    • Topical formulations explored for atopic dermatitis, urticaria, contact dermatitis

Pharmacokinetics

PropertyCromolyn SodiumNedocromil SodiumLodoxamide
Absorption (oral)Poor (<1% bioavailable)N/ANot systemically absorbed
Peak effect2–4 weeks for full effect1–2 weeksDays
MetabolismNot metabolizedMinimalNot applicable
EliminationFecal (unabsorbed drug)Renal (minor)Local use
Half-life1.5 hours (inhaled)~3 hoursNot systemically measured



Dosing Considerations

  • Prophylactic use only; not effective during acute attacks

  • Must be administered regularly (not PRN) to maintain efficacy

  • Onset of clinical benefit takes several days to weeks

Adverse Effects

Generally well tolerated due to minimal systemic absorption.

SystemAdverse Effects
RespiratoryCough, throat irritation, wheezing (inhaled forms)
GastrointestinalNausea, abdominal discomfort (oral cromolyn)
DermatologicSkin rash (rare), urticaria (hypersensitivity)
OphthalmicBurning/stinging upon application (eye drops)
SystemicHeadache, joint pain (rare)


Hypersensitivity reactions are rare but may include anaphylaxis. Discontinue immediately if signs appear.

Contraindications

  • Known hypersensitivity to the drug or any of its components

  • Inability to cooperate with inhaled therapy (in pediatric or cognitively impaired patients)

  • Acute asthma attack or acute allergic episode requiring immediate relief

Drug Interactions

  • No major systemic drug interactions due to poor bioavailability

  • Inhaled corticosteroids may enhance overall anti-inflammatory effect when used in combination

  • Ophthalmic and nasal formulations may be co-administered with antihistamines or corticosteroids

  • Avoid concurrent use with MAO inhibitors or tricyclics in oral forms due to potential GI irritation

Monitoring Parameters

  • Symptom diary to assess efficacy (rhinitis, conjunctivitis, asthma)

  • Adherence monitoring due to multiple daily doses required

  • Peak expiratory flow (PEF) and lung function for inhaled agents

  • GI symptom scoring in mastocytosis and food allergy patients

Special Populations

Pediatrics

  • Safe and effective for asthma and allergic eye conditions

  • Cromolyn sodium often used due to minimal side effects

Pregnancy

  • Category B (cromolyn): No evidence of teratogenicity

  • Preferable over systemic antihistamines for allergic rhinitis during pregnancy

Elderly

  • No dose adjustment needed; consider ease of use in inhaled/nasal forms

Advantages of Mast Cell Stabilizers

  • Excellent safety profile

  • Non-sedating (unlike some antihistamines)

  • No significant systemic adverse effects

  • Useful as steroid-sparing agents

  • Suitable for long-term use in children

Limitations

  • Slow onset of action

  • Requires multiple daily doses

  • Less effective as monotherapy in moderate/severe disease

  • Not effective in acute settings (e.g., asthma attacks)

  • Discontinued availability of inhaled forms in some countries (e.g., nedocromil inhaler)

Comparative Insights

AgentOnset of ActionRouteBest UsePotency
Cromolyn sodium1–2 weeksInhaled, oral, topicalMild asthma, mastocytosisModerate
Nedocromil sodium4–7 daysOphthalmic, inhaledAllergic eye conditions, asthmaHigher than cromolyn
Lodoxamide2–3 daysOphthalmicVernal conjunctivitisHigh (ocular)
KetotifenWithin hoursOphthalmicRapid relief + prevention (dual agent)Dual-action



Regulatory Approvals

  • Cromolyn sodium:

    • Approved by FDA, EMA, and Health Canada for asthma, rhinitis, conjunctivitis, mastocytosis

  • Nedocromil:

    • Approved for ophthalmic use in US and EU; inhaled formulation phased out

  • Lodoxamide:

    • Approved for seasonal allergic conjunctivitis globally

Research and Development

  • Nanoformulations of mast cell stabilizers to improve ocular retention

  • Liposomal cromolyn for targeted delivery in pulmonary fibrosis and COPD

  • Intranasal formulations under investigation for migraine and nasal polyps

  • Studies exploring mast cell stabilizers in long COVID-19, MCAS (mast cell activation syndrome)

  • Trials in interstitial cystitis, atopic dermatitis, and chronic urticaria

Summary: Role in Therapy

Mast cell stabilizers offer safe, non-systemic prevention of allergic and mast-cell mediated conditions. They are most effective when used as:

  • Maintenance therapy for mild allergic diseases

  • Prophylactic agents before known allergen exposure

  • Adjuncts to antihistamines and corticosteroids

  • Alternatives in pediatrics and pregnancy




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