An Introduction to Nedocromil
Nedocromil sodium is an anti-inflammatory drug classified as a pyranoquinolone, and it is recognized for its role as a mast cell stabilizer [1.2.4, 1.2.8]. It was historically used as a maintenance therapy to prevent the symptoms of mild to moderate asthma in adults and children, available as an inhaler under the brand name Tilade [1.2.8, 1.3.3]. It was also formulated as an eye drop (brand name Alocril) for treating allergic conjunctivitis [1.2.8, 1.3.7]. An important distinction is that nedocromil was a prophylactic medication, designed to prevent asthma attacks and bronchospasm with regular use, rather than treating an acute attack that has already started [1.3.4]. Despite its efficacy and strong safety profile, the inhaled form of nedocromil was discontinued in the U.S. and other regions around 2008 because its inhaler used chlorofluorocarbons (CFCs) as a propellant, which were phased out due to environmental concerns [1.7.1, 1.7.4].
The Primary Mechanism: Mast Cell Stabilization
The cornerstone of nedocromil's action is its ability to stabilize mast cells [1.2.3]. In an allergic response, mast cells degranulate and release a cascade of inflammatory mediators when exposed to an allergen. Nedocromil prevents this from happening [1.2.8]. By stabilizing the mast cell membrane, it effectively suppresses the release of pre-formed mediators like histamine and tryptase [1.2.3]. This action directly mitigates the immediate symptoms of an allergic reaction, such as itching, swelling, and bronchoconstriction. Furthermore, it inhibits the synthesis of other pro-inflammatory substances like prostaglandins and leukotrienes, which are involved in the later phases of the allergic response [1.2.3, 1.2.4].
Broader Anti-Inflammatory Effects
While mast cell stabilization is its primary role, nedocromil's mechanism is broader and affects a wide range of cells involved in the inflammatory process of asthma [1.2.3, 1.2.4].
Impact on Eosinophils, Neutrophils, and Macrophages
Nedocromil inhibits the activity of several other key inflammatory cells. It has been shown to decrease the chemotaxis (the directed movement of cells) and activation of eosinophils [1.2.5]. Eosinophils are crucial players in the chronic inflammation associated with asthma. The drug also inhibits the activation and mediator release from neutrophils, macrophages, monocytes, and platelets [1.2.4]. For instance, in vitro studies demonstrated that nedocromil inhibits the release of beta-glucuronidase from macrophages [1.2.5]. This wide-ranging inhibitory effect helps to quell the overall inflammatory environment in the airways.
Modulation of Neuronal Pathways
A significant part of nedocromil's efficacy, particularly in managing bronchial hyperresponsiveness, may be due to its effect on neural pathways [1.2.7]. The mechanism is thought to involve the inhibition of axon reflexes and the release of sensory neuropeptides, such as substance P, neurokinin A, and calcitonin-gene-related peptides [1.2.4, 1.2.6]. These neuropeptides can cause bronchoconstriction and airway inflammation. By modulating the activity of sensory C-fibers in the airways, nedocromil can reduce the cough and bronchoconstriction triggered by irritants [1.2.6].
The Role of Chloride Ion Channels
A unifying hypothesis for nedocromil's diverse effects lies in its ability to inhibit chloride ion flux in mast cells, epithelial cells, and neurons [1.2.1]. By acting on these chloride channels, nedocromil essentially raises the threshold at which these cells will respond to stimulation [1.2.2]. For example, in an isolated vagus nerve preparation, the drug produced an initial transient opening of the chloride channel followed by a refractory period where further action potentials could not be generated [1.2.2]. This action on a mechanism that is only operative when a cell is activated may explain the drug's excellent safety profile and lack of toxicity [1.2.2].
Comparison Table: Nedocromil vs. Cromolyn Sodium
Nedocromil is often compared to cromolyn sodium, another mast cell stabilizer. While they share a similar primary function, there are key differences.
| Feature | Nedocromil Sodium | Cromolyn Sodium |
|---|---|---|
| Classification | Pyranoquinolone [1.3.5] | Chromone [1.3.5] |
| Potency | Generally considered more potent in stabilizing mast cells and other inflammatory cells [1.2.6]. | Less potent than nedocromil [1.2.6]. |
| Dosing (Ophthalmic) | Typically twice a day [1.4.1]. | More frequent, often 4 to 6 times a day [1.4.1]. |
| Efficacy | Some studies show it to be more effective, especially in controlling symptoms [1.4.2]. | Effective, but some comparative studies found it less effective than nedocromil [1.4.2, 1.4.5]. |
| Side Effect Profile | Most noted for an unpleasant taste in the mouth [1.6.7]. | Most noted for temporary stinging or burning upon application [1.4.1]. |
| Approved Age (Asthma) | Approved for children 12 years and older in the US [1.4.3]. | Approved for children 2 years and older [1.4.3]. |
Pharmacokinetics: Absorption, Distribution, and Excretion
Nedocromil has very low systemic absorption, which contributes to its high safety margin [1.5.1]. When administered via an inhaler, only about 5-10% of the dose is absorbed, primarily from the respiratory tract [1.5.1, 1.5.7]. The portion that is swallowed has even lower absorption from the GI tract (2-3%) [1.5.4]. When used as an ophthalmic solution, less than 4% is systemically absorbed [1.5.6]. The drug is not metabolized in the body and is excreted unchanged, with about 70% eliminated in the urine and 30% in the feces [1.2.4, 1.5.6]. It has a plasma half-life of approximately 1.5 to 3.3 hours [1.5.4].
Side Effects and Safety Profile
Nedocromil is generally very well-tolerated [1.5.1]. The most common side effects are often mild and related to the administration route. For the inhaled form, an unpleasant or bitter taste was the most frequently reported side effect, along with headache, cough, and rhinitis [1.6.7]. For the ophthalmic solution, common side effects included headache (reported in up to 40% of patients), ocular burning or stinging, and a stuffy nose [1.6.2, 1.6.5]. Serious adverse effects were very rare, and only a very small percentage of patients (2-3%) discontinued therapy due to side effects [1.2.7].
Conclusion
In summary, the mechanism of action of nedocromil is that of a broad-spectrum anti-inflammatory agent. Its primary function as a mast cell stabilizer is supported by a deeper mechanism involving the inhibition of chloride channels, which prevents the activation of mast cells, eosinophils, and even sensory neurons. This multifaceted action allowed it to effectively prevent the symptoms of mild to moderate asthma and allergic conjunctivitis. While it has been largely removed from the market due to the phase-out of CFC propellants, its story remains an important chapter in the pharmacology of anti-inflammatory treatments.
For more detailed pharmacological data, please see its entry in the DrugBank database.
