What are some examples of mast cell inhibitors?

Mast Cell Inhibitors

The primary mast cell inhibitors available for clinical use include cromolyn sodium (oral and inhaled), H1 and H2 antihistamines, leukotriene modifiers, omalizumab, and corticosteroids, with cromolyn sodium being the only FDA-approved agent that directly prevents mast cell mediator release. 1, 2

Direct Mast Cell Stabilizers

Cromolyn Sodium

• Cromolyn sodium is the prototype mast cell stabilizer that directly inhibits mediator release from mast cell membranes by preventing degranulation 2, 3
• Available in both oral and inhaled formulations, with oral cromolyn specifically FDA-approved for mastocytosis 2
• Mechanism: Inhibits release of histamine, leukotrienes (SRS-A), and other mediators from sensitized mast cells without intrinsic antihistamine, vasoconstrictor, or glucocorticoid activity 2
• For mast cell activation syndrome (MCAS), start at 20-40 mg four times daily and gradually titrate up to 200 mg four times daily over weeks, given before meals and at bedtime 1, 4
• Requires at least 1 month trial to assess efficacy 1
• Particularly effective for gastrointestinal symptoms (diarrhea, abdominal pain, nausea, vomiting) and can help with cutaneous symptoms and cognitive function 1, 2
• Major limitation: Only 0.28-0.50% oral absorption, with remainder excreted in feces 2
• Topical formulations (cream, lotion) can be used for cutaneous symptoms 1

Nedocromil

• Similar mechanism to cromolyn, stabilizing mast cells and interfering with chloride channel function 1
• Requires inhaled administration 4 times daily 1

Ketotifen

• Sedating H1 antihistamine with mast cell stabilizing properties 1
• Available as compounded tablets in the United States (FDA-approved only for allergic eye disease) 1
• Treats dermatologic, gastrointestinal, and neuropsychiatric symptoms 1, 5

Indirect Mast Cell Inhibitors (Mediator Blockers)

H1 Antihistamines

• Second-generation non-sedating agents (fexofenadine, cetirizine) are preferred and often used at 2-4 times FDA-approved doses 1, 5
• Reduce dermatologic manifestations (flushing, pruritus, urticaria), tachycardia, and abdominal discomfort 1
• First-generation agents (diphenhydramine, hydroxyzine, chlorpheniramine) cause sedation and cognitive decline, particularly problematic in elderly patients 1, 5

Cyproheptadine

• Dual H1 blocker and serotonin receptor antagonist 1, 5
• Specifically recommended for diarrhea and nausea in MCAS patients 1, 5, 6

H2 Antihistamines

• Ranitidine or famotidine for gastrointestinal symptoms and gastric hypersecretion 1
• Combined H1/H2 blockade more effective than H1 alone for severe pruritus and wheal formation 1

Leukotriene Modifiers

• Montelukast, zafirlukast, or zileuton block the leukotriene pathway 1
• Most effective when combined with H1 antihistamines, particularly if urinary LTE4 levels are elevated 1, 5
• Reduce bronchospasm and gastrointestinal symptoms 1

Omalizumab (Anti-IgE Therapy)

• Monoclonal antibody that binds free IgE, preventing FcεRI binding and reducing mast cell activation threshold 1
• Reserved for MCAS resistant to mediator-targeted therapies due to high cost 1, 4
• Prevents spontaneous anaphylaxis episodes, reduces emergency department visits 1
• Subcutaneous injection every 2-4 weeks 1

Corticosteroids

Systemic Steroids

• May help refractory symptoms but should be tapered quickly to limit adverse effects 1
• For refractory cases: 0.5 mg/kg/day oral prednisone with slow taper over 1-3 months 1, 5
• Can give 50 mg prednisone at 13,7, and 1 hour before procedures when mast cell activation is problematic 1

Intranasal Corticosteroids

• Effective for rhinitis symptoms with strong safety profile at recommended doses 1
• No clinically significant effects on HPA axis, bone density, or growth at standard doses 1

Cytoreductive and Signal Transduction Inhibitors

For Advanced Systemic Mastocytosis

• Midostaurin: Multikinase inhibitor approved for advanced SM, targets wild-type and D816V Kit 1
• Masitinib: Tyrosine kinase inhibitor for wild-type Kit, but asthenia is common side effect 1
• Imatinib: Not indicated if D816V mutation present (causes resistance) 1
• Avapritinib and DCC2618: Selective D816V Kit inhibitors in clinical trials 1
• IFN-α and cladribine: Used for aggressive SM refractory to antimediator therapy 1

Emerging and Alternative Agents

Natural Flavonoids

• Quercetin and luteolin are more potent than cromolyn in blocking human mast cell cytokine release in vitro 7, 8
• Quercetin inhibits IL-8, TNF, IL-6, calcium influx, and NF-κB activation more effectively than cromolyn 7
• Luteolin significantly more potent than cromolyn at inhibiting histamine, tryptase, and multiple cytokines 8
• Major limitation: Poor oral absorption requires liposomal formulations 8
• Quercetin showed clinical benefit in pilot trials for contact dermatitis and photosensitivity 7

Aspirin

• May reduce flushing and hypotensive episodes associated with prostaglandin D2 secretion 1, 5
• Critical caveat: Can trigger mast cell activation in some patients; must introduce in controlled clinical setting 1, 4, 5

Anticholinergics

• Ipratropium bromide for rhinorrhea, no effect on mast cell degranulation itself 1

Important Clinical Considerations

Cromolyn's effectiveness in mice is questionable - studies show it fails to inhibit IgE-dependent mast cell responses in mice under most conditions tested, despite effectiveness in rats 9. This limits translational research applicability.

Prophylactic use is critical - H1/H2 antihistamines work better prophylactically than acutely because once mediators are released and bound to receptors, blocking is ineffective 1

Introduce medications cautiously - MCAS patients may experience paradoxical reactions; new medications should be started in controlled settings with emergency equipment available 4, 5, 6

Epinephrine autoinjectors are mandatory for patients with history of systemic anaphylaxis or airway angioedema 1, 4, 5