Allergic conjunctivitis is a group of conjunctival allergic diseases caused by external allergens, including Seasonal Allergic Conjunctivitis (SAC) and Perennial Allergic Conjunctivitis (PAC), Vernal Catarrh Keratoconjunctivitis (VKC), Giant Papillary Conjunctivitis (GPC), and Atopic Keratoconjunctivitis (AKC). Vernal Catarrh Keratoconjunctivitis (VKC), Giant Papillary Conjunctivitis (GPC), and Atopic Keratoconjunctivitis (AKC). In recent years, the incidence of allergic conjunctivitis has increased significantly due to natural environmental changes and the wearing of corneal contact lenses, and has become one of the most important diseases affecting the quality of life of patients.
According to the different pathogenesis, allergic conjunctivitis can be divided into acute and chronic, the former is dominated by IgE-mediated type I allergic reactions, including SAC and PAC; the latter has the participation of type IV allergic reactions, including VKC, GPC and AKC, in addition to type I allergic reactions.
At present, the treatment of metaplastic conjunctivitis is still based on local drugs, and the commonly used ocular anti-allergy drugs mainly include mast cell stabilizers, antihistamines, dual-action drugs, glucocorticoids, non-steroidal anti-inflammatory drug (NSAID), local vasoconstrictors, immunosuppressants, artificial As an important adjunct in the treatment, tear solution has the role of improving the patient’s symptoms, protecting the cornea and preventing the occurrence of dry eyes. The selection of clinical anti-allergic drugs should be based on the type of disease, the degree of lesion, and also combined with the drug mechanism of action and other comprehensive considerations.
I. Mast cell stabilizers
There are abundant mast cells in the conjunctival tissue, about 5000 cells/mm2. Activated mast cell degranulation releases a large amount of histamine and inflammatory mediators, causing a series of allergic signs and symptoms. Mast cell membrane stabilizers work by inhibiting the inward flow of calcium ions to stabilize mast cells and prevent the release of histamine and other mediators. However, mast cell stabilizers can only prevent the release of inflammatory mediators from mast cells, but have no effect on the released inflammatory mediators, and the clinical effect is relatively slow.
1, sodium cromolyn sodium: clinical application for many years, the effect is related to the concentration of drugs, commonly used clinical concentration of 2% and 4%, the latter clinical effect is better, the effect of chronic metaplasia (such as GPC, AKC, VKC) is better, the role of prevention and maintenance treatment, safer, 2 to 4 years old children can be applied.
2.lodoxamide: The mechanism of action is the same as sodium cromoglycate, but the effect of inhibiting the release of histamine from mast cells is 2500 times that of sodium cromoglycate, and it can effectively reduce the level of fibrinolytic enzymes in tears and the aggregation of inflammatory cells, so as to reduce the damage of inflammatory mediators on tissues. 0.1% lodoxamide has a stronger effect on chronic allergic conjunctivitis (GPC, AKC, VKC) than sodium cromoglycate. Lodosamide 0.1% eye drops can be used for adults and children over 2 years of age 4 times daily for 3 months. Very few patients have experienced corneal epithelial erosion, visual fatigue, conjunctival edema, and allergic reactions.
3.Pemirolast: It is a pyrimidine compound, which has been used for the treatment of bronchial asthma, allergic rhinitis, AKC and VKC in Japan since 1991. 0.1% pimecrolimus eye drops are used to treat AKC, VKC and other allergic conjunctivitis, 2 times/d for 4 weeks. Less than 5% of patients develop conjunctival congestion and irritation after eye drops, and allergic eyelid dermatitis may also occur.
Topical antihistamines
In allergic ocular surface diseases, histamine is the most important inflammatory mediator released by activated mast cells. 80% to 90% of clinical allergy symptoms are caused by histamine, which binds to histamine receptor 1 (Hr1) to produce symptoms of itchy eyes and to histamine receptor 2 (Hr2) to cause vasodilation and tissue congestion. binding, causing vasodilation, tissue congestion, edema, and increased secretion.
Currently, local antihistamines are mainly H1r blockers, which have obvious antipruritic effect but no vasoconstrictive effect, so they are often used in combination with vasoconstrictive agents.
1, levocabastine (levocabastine): highly selective H1r blocker, potent antihistamine, the inhibitory effect of H1r than astemizole 65 times stronger, rapid onset of action, antipruritic effect lasting, no effect on the nerve center [5].
It was marketed in the United States in 1994 and is superior to sodium cromoglycate in suppressing ocular itch, reducing ocular congestion, edema and tearing, and also improving photophobia in chronic allergic conjunctivitis and VKC. Levocabastine can also inhibit the release of histamine in the conjunctiva and increase the concentration of histamine in the tear fluid to prevent and treat AKC. the clinical concentration of eye drops is 0.05%, after dropping a few eyes may have blurred vision, dry eyes, congestion, dry mouth, lacrimation and other discomfort.
2, emedastine (emedastine): the selective blocking effect of H1r is stronger than levocabastine, while the inflammatory mediators such as interleukin-6 (interleukin-6, IL-6) and interleukin-8 (interleukin-8, IL-6) have a strong inhibitory effect, but also has a weak anticholinergic, anti bradykinin and anti- 5-HT activity.
Emedastine can be used for the prevention and treatment of various types of allergic conjunctivitis. Clinical application showed that 0.05% emetine relieved eye itching and congestion to a greater extent than 0.05% levocabastine, and significantly relieved patients’ signs and symptoms after 6 weeks of treatment. 0.05% emetine lasted for 4 h after topical application, 2 to 3 times daily. A few patients showed headache, weakness and dermatitis after eye drops.
Third, dual-action drugs
This is a new class of anti-allergic drugs, with antihistamine and stabilization of mast cell membranes; in addition, they also have inhibitory effects on a variety of inflammatory response pathways, known as dual-action drugs.
1, olopatadine (olopatadine): a new type of fast-acting, long-acting dual-acting anti-allergy drugs, both highly selective inhibition of H1r activity and stabilization of mast cell membranes, but also inhibit the conjunctival epithelial cells and mast cells to IL-6, IL-8, tumor necrosis factor and other inflammatory factors released. It takes effect 3~5min after administration, and has obvious effect of stopping itching and reducing conjunctival congestion in the treatment of allergic conjunctivitis, and the efficacy can last for more than 8h.
The concentration of topical eye drops is 0.05%~0.10%, twice daily. Clinical application shows that 0.1% olopatadine is more effective and better tolerated than 2% nedolimus and 0.025% ketotifen in the treatment of allergic conjunctivitis; less than 5% of patients have transient burning sensation, dry eyes, stinging and foreign body sensation, etc.
2, ketotifen (ketotifen): belongs to the benzene propane heptathiophene drugs, with obvious stabilization of mast cell membrane and H1r antagonism, and inhibit the formation of leukotrienes and other slow reactants, so as to inhibit the edema and exudation of such media caused by the tissue, has a strong anti-allergic effect. 0.025% ~ 0.050% ketotifen eye drops usage for four times a day.
3, azelastine (azelastine): H1r blocker, but also can stabilize mast cell membranes, reduce the activation of eosinophils and T lymphocytes, inhibit the release of a variety of inflammatory mediators, and reduce the expression of adhesion factors. It was initially used for oral or nasal drops for the treatment of allergic rhinitis, and was approved by the FDA in 2000 for the treatment of allergic conjunctivitis with good anti-itch effect and also for prevention.
It is effective in all types of allergic conjunctivitis, with a rapid onset of action lasting 8-10 h. It can significantly reduce signs and symptoms such as itching, congestion, bulbar conjunctival edema and tearing. About 20% of patients have abnormal taste sensation after eye drops.
4, nedocromil (nedocromil): once considered a mast cell membrane stabilizer, it is now believed that it has a dual role of H1r blocking and stabilizing mast cells; it can also inhibit the activation and aggregation of neutrophils, eosinophils, macrophages, mast cells and platelets and other inflammatory cells, can inhibit the early and late allergic conjunctival congestion and edema, eyelid edema and eosinophil infiltration. It was approved by the FDA in the United States in 2000.
Nedolomib 2% eye drops are used to treat VKC and other allergic eye diseases; 80% of SAC patients show significant improvement in signs and symptoms after application. Nedolomil eye drops have temporary eye irritation and burning sensation after use.
IV. Non-steroidal anti-inflammatory drug (non-steroid anti-inflammatory drug, NSAID)
NSAID inhibits prostaglandin production by inhibiting the synthesis of cyclooxygenase, which has the effect of anti-inflammation and anti-itch. Topically applied NSAIDs in the eye include ketorolac, diclofenac, flurbiprofen, etc. Clinical studies have confirmed that these drugs can reduce symptoms such as itching and conjunctival congestion caused by VKC and seasonal antigens, but it should be noted that these drugs themselves are irritating and toxic to the ocular surface, and some patients are allergic to the drugs themselves.
V. Local vasoconstrictors
Currently, the commonly used ocular local vasoconstrictors are mainly azole derivatives, including hydroxymetazoline and naphthazoline, both of which are sympathomimetic drugs with vasoconstrictor effects, acting directly on the α-adrenergic receptors of vascular smooth muscle, causing vasoconstriction and reducing congestion and edema caused by inflammatory reactions, but they are ineffective in reducing allergy, and usually need to be used simultaneously with antihistamines or using antihistamine-vasoconstrictor Compounding.
Hydroxyzoline and 0.025% naphthazoline can significantly reduce conjunctival congestion after topical application, with onset of action within minutes, and are indicated for all types of ocular surface allergic diseases, 1 to 2 drops per dose, 3 to 4 times daily.
Adverse effects of topical vasoconstrictors include eye burning, stinging, and pupil dilation, and are therefore contraindicated in patients with closed-angle glaucoma, and should be used with caution in patients with hypertension, arrhythmia, and hyperthyroidism. Patients with hypertension, cardiac arrhythmia, hyperthyroidism, etc. may also experience rebound congestion or drug conjunctivitis with long-term use.
Glucocorticoids
If the above-mentioned drugs are not effective, glucocorticoids can be considered, which play an immunosuppressive role by inhibiting the release of inflammatory cell mediators, suppressing lymphocytes and the complement system, reducing antibody formation, inhibiting phagocytosis, and stabilizing lysosomal membranes. However, long-term topical application has side effects such as increased intraocular pressure, recurrence of infection and complications of cataract. Glucocorticosteroids are only suitable for short-term treatment of severe allergic eye diseases, and can be administered in large doses for a short period of time, and then reduced to discontinued after the symptoms are controlled, while other anti-allergic drugs are added to maintain the efficacy.
In recent years, some new glucocorticosteroids have been introduced, which have better anti-inflammatory and anti-allergic activities, and less side effects such as elevated IOP.
Rimexolone: It is a derivative of strong prednisolone, which is rapidly inactivated after entering the anterior chamber. It is a glucocorticoid that can be metabolized locally, and the metabolites in vivo have no activity.
1% limetholone is used for the treatment of moderate to severe allergic eye disease 4 times a day. Long-term application can also lead to clouding of the posterior lens capsule and induce eye infections.
2. Loteprednol: It can inhibit the inflammatory reaction of the eye caused by various stimuli. Its mechanism of action is to induce the synthesis of phospholipase A2 inhibitor protein, thus inhibiting the activity of phospholipase A2, which prevents the conversion of membrane phospholipids into arachidonic acid and blocks the synthesis of prostaglandins and leukotrienes. In vivo cortriptyline is quickly hydrolyzed by tissue esterases and can be easily excreted from the body. The metabolism occurs in the cornea after topical drops, so the atrial water concentration is extremely low, and the chance of causing IOP elevation is very small.
It is the first glucocorticosteroid approved by FDA for the treatment of allergic conjunctivitis, and can be used as a preventive medicine. Long-term use of this drug can also cause an increase in intraocular pressure, but the incidence is lower than that of prednisolone; it can also lead to cataract formation, secondary ocular infections, and delayed wound healing. The use of this drug can lead to perforation in patients with corneoscleral thinning.
VII. Immunosuppressants
1, cyclosporine (CsA): an immunosuppressant extracted from the fungus, local application can inhibit the proliferation of Th2 lymphocytes and IL-2 production; it also inhibits the release of histamine from mast cells and basophils, and reduces the aggregation and role of eosinophils in the conjunctiva. Topical 0.5% to 2.0% CsA drops 4 times daily can be used to treat severe VKC and reduce the proliferation of conjunctival papillae in patients with VKC . For glucocorticoid-dependent patients, CsA can replace glucocorticoids or reduce the amount of glucocorticoids.
2, tacrolimus (FK506): macrolide antibiotics, while having a strong immunosuppressive effect, mainly inhibiting T lymphocyte activation and proliferation, inhibiting the production of lymphokines; also inhibits the release of histamine and other inflammatory mediators from mast cells. 0.1% FK506 eye drops can significantly reduce the signs and symptoms of allergic conjunctivitis.