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Anti-allergic agents are medications used to treat allergic reactions. Anti-allergic agents have existed since 3000 B.C in countries such as China and Egypt. It was not until 1933 where antihistamines, the first type of anti-allergic agents were developed ^[1]. Allergies can be caused by environmental factors, certain food products and medications. Common allergic diseases include allergic rhinitis, allergic asthma, and atopic dermatitis. Symptoms can vary in severity, including runny nose, watery eyes, itchiness, coughing, and shortness of breath. More than one-third of the world's population is currently being affected by one or more allergic conditions. ^[2]

Commonly used anti-allergic agents include antihistamines, decongestants, corticosteroids, leukotriene pathway modifiers and mast cell stabilizers. Antihistamines and decongestants are generally the first-line treatment in mild to moderate allergic reactions. Corticosteroids are generally indicated for moderate cases. In severe cases, adrenaline is used to reduce swelling and aid breathing. Allergen immunotherapy is an alternative treatment considered in some patients, with a success rate of 80%-90% in reducing symptoms ^[3], but requiring a much longer duration of therapy. The choice of medications depends on the disease to be treated, its severity and patient factors.

Allergy

Allergies, also known as type 1 hypersensitivity, are a type of immune response which takes place when our body’s protective mechanism defends us against triggers called allergens.

Common causes

An allergic reaction can be caused by direct contact with an allergen. For example, through consuming a certain food, inhalation of pollens or dust mites, or direct contact by touching a certain material. A family history of allergies also leads to a higher risk of developing allergic diseases. ^[4]

Mechanism

When a person comes in contact with a specific trigger, their immune system “overreacts, " perceiving the matter as a threat, thus producing antibodies called immunoglobulin E (IgE). When these IgE molecules bind to mast cells, immune cells found mainly in the skin, respiratory tract and digestive tract triggers the release of histamine (a chemical messenger) and other chemicals that guards our immune system. ^[3] The binding of histamine to H-1 receptors activates a chain of events (scientifically called cellular signaling cascades). This may include the increase in level of membrane permeability, causing fluid to pervade from capillaries to surrounding tissues in the nose, thus causing a runny nose. Subsequently, it may also dilate vessels (vasodilation), and cause inflammation and redness on skin.

Types

Allergic reactions can range from mild to severe. Some common allergic diseases include allergic rhinitis, allergic asthma, allergic conjunctivitis and atopic dermatitis. They are further generalized into Each condition presents its own set of symptoms. In severe cases, certain allergies can lead to a life-threatening allergic reaction called anaphylaxis. This is a medical emergency that requires immediate treatment, as it can be fatal if not treated properly. ^[2]

Symptoms can vary in severity from person to person. Allergies can affect daily activities, sleep quality, work or school performance, and mood, directly impacting an individual’s quality of life. ^[8] Therefore, proper diagnosis and management are crucial for individuals with allergic diseases.

Management

The most effective management of allergies is avoiding allergens to reduce the risk of an allergic reaction. If the allergic reaction continues, medications may be needed to help reduce symptoms.

Common anti-allergic agents

Antihistamines

Antihistamines, specifically H1-antihistamines, are medicines which provide relief for allergic symptoms such as runny nose, sneezing, itching, and watery eyes from hay fever (or generally called ' seasonal allergies'). They are usually the first line of medications prescribed by a general practitioner, or a pharmacist for allergies in a community pharmacy. H1-antihistamines are further split into three groups known as the first-generation, second-generation and third-generation antihistamines. Another type of antihistamines known as H2-antihistamines are used to treat gastrointestinal conditions caused by excessive stomach acid. ^[9]

Mechanism

H-1 antihistamines work by blocking the effects of histamine. H-1 receptors are histamine receptors expressed in smooth muscles, vascular endothelial cells, the heart, and the central nervous system ^[10]. The binding of histamine to H-1 receptors induce a range of cellular signaling cascades such as vasodilation and membrane permeability. H-1 antihistamines inhibit histamine from binding to the H-1 receptors, preventing this chain of events from happening thus preventing allergic symptoms.

First-generation antihistamines can easily cross the blood-brain barrier into the central nervous system to reach the H-1 receptors within, often causing drowsiness ^[10] . Second-generation antihistamines selectively bind to the peripheral H-1 receptors outside the blood-brain barrier, therefore they are less likely to cause sedation. First-generation antihistamines usually last around 4-6 hours whilst second-generation antihistamines work for 12-24 hours ^[10]. Third generation antihistamines are metabolites of the second-generation antihistamines but without cardiac toxicity ^[11].

Indications and route of administration

Antihistamines are generally indicated for the alleviation of conditions such as allergic rhinitis, allergic conjunctivitis, or atopic dermatitis that are characterised by type 1 hypersensitivity. ^[12] Other indications may include nausea and vomiting. Antihistamines are usually for short-term treatment. Chronic allergies, such as allergic asthma may include health problems which antihistamines alone cannot treat. ^[12] The routes of administration of antihistamines are usually oral, intranasal, and topical.

Side effects

Side effects may exist more in first-generation antihistamines, for example drowsiness, blurred vision and dry mouth. Other common side effects for all generations may include gastrointestinal side effects, headaches, tiredness and dizziness. ^[12]

Pregnancy: Current studies suggest that antihistamines are generally safe to use during pregnancy though second-generation antihistamines are more preferred due to their lack of sedation ^[13]. However, please consult your family doctor for their professional advice.

Decongestants

Decongestant, or nasal decongestants is a pharmaceutical drug which relieves nasal obstruction due to inflammation in the upper respiratory tract. They are often used as the first-line therapy for allergic rhinitis.

Mechanism

Decongestants work by binding to the alpha-adrenergic receptors in the sympathetic nervous system (controls our body’s ‘fight or flight’ response) on the smooth muscle cells situated on the blood vessels in nasal passages. This causes vasoconstriction, the narrowing or constriction of blood vessels. This then reduces blood flow to the nasal mucosa and decreases swelling. Decongestants help open up nasal passages thus allowing for easier breathing. However it must be noted that decongestants do not treat the underlying cause of congestion, but rather a temporary relief only.

Indications and route of administration

Decongestants are mainly used in conductions such as common cold, allergic rhinitis, and sinusitis. They provide temporary relief from symptoms of nasal congestion, such as a blocked nose or sinus pressure. However, prolonged use of more than 10 days may result in rhinitis medicamentosa (inflammation of nasal mucosa). Therefore, decongestants should not be taken for longer than a week. Decongestants are available through various forms namely through oral and intranasal routes.

Combination therapy with antihistamines

Antihistamines and decongestants can be used as a combination to treat nasal congestion, runny nose, and sneezing symptoms caused by common cold and hay fever.

Side effects

Common side effects of nasal decongestants may include local irritation, increased blood pressure, increased heart rate, dryness of nasal passages, rebound congestion, and difficulty passing urine (in men). Less common side effects include dizziness, nausea and insomnia.

Precautions

Decongestants are contraindicated in patients with hypertension, heart disease, diabetes, benign prostate hypertrophy (BPH), liver or kidney problems and thyroid disease.

Pregnancy: avoid use during pregnancy as it may cause vasoconstriction of uterine arteries thus reducing fetal blood supply.

Corticosteroids

Corticosteroids, specifically glucocorticoids, are anti-inflammatory agents used to treat allergic conditions. Corticosteroids can be classified into mineralocorticoids and glucocorticoids. Mineralocorticoids regulate salt and water balances, while glucocorticoids play a role in glucose homeostasis and regulating the activation of immune cells. The word “glucocorticoid” is derived from “glucose + cortex + steroid” ^[14], representing its role in the regulation of glucose metabolism, its biosynthesis in the adrenal cortex (which produces hormone), and the steroid structure it possesses.

Mechanism

Glucocorticoids bind to glucocorticoid receptors to exert their effects. The receptor-glucocorticoid complex activates transcription of anti-inflammatory genes in the nucleus (a process known as transactivation) and represses the expression of pro-inflammatory factors in the cytosol (a process known as transrepression) ^[15]. Ultimately, they can decrease the synthesis and release of inflammatory mediators such as mast cells, eosinophils, dendritic cells, and cytokines from macrophages.

Indications

Glucocorticoids have a wide range of therapeutic uses. Since they suppress inflammation and reduce the signs and symptoms such as swelling, redness and itching, they are commonly used to treat allergic conditions including allergic rhinitis, asthma and eczema. Glucocorticoids can be given via different routes of administration, depending on the condition and severity. The most common ones are oral, inhalation, topical and injection.

Side effects

Common side effects of glucocorticoids include fluid retention, mood changes and weight gain. The side effects are associated with the dosage, type of drug used and the duration of treatment. Systemic corticosteroids are not considered first-line therapy for chronic management due to common and significant risks of adverse reactions. These include osteoporosis, cataracts, depressed immunity and Cushing’s syndrome.

Leukotriene pathway modifiers

Leukotrienes are lipid mediators formed from arachidonic acid by the enzyme 5-lipoxygenase, causing constriction of the airway smooth muscle, increased mucus secretion and enhanced immune response, resulting in allergic inflammation ^[16]. Leukotriene pathway modifiers can be classified into two types. The cysteinyl leukotriene receptor antagonists, including Montelukast and Zafirlukast, bind to leukotriene receptors to inhibit bronchoconstriction and other effects of leukotrienes ^[17]. Zileuton is a 5-lipoxygenase inhibitor which directly prevents the synthesis of leukotrienes. All three leukotriene pathway modifiers are indicated for the treatment of chronic asthma, but only Montelukast is approved to treat allergic rhinitis ^[17]. It has a similar effectiveness as antihistamines, but is less effective than nasal corticosteroids in relieving the symptoms and improving the quality of life in patients with seasonal allergic rhinitis ^[18].

Mast cell stabilizers

Mast cell stabilizers inhibit the release of allergic and inflammatory mediators, helping to prevent and treat allergic conditions. They work by blocking a calcium channel which is essential for mast cell degranulation ^[19], inhibiting the release of mediators like histamine and leukotrienes from mast cells. Examples of mast cell stabilizers include cromolyn sodium and nedocromil sodium. They are commonly used in eye drops to treat allergic conjunctivitis, in intranasal formulations for allergic rhinitis and given by inhalation for asthma. Common side effects include irritation, itching, and cough.

Less common anti allergic agents

Adrenaline

Adrenaline (or epinephrine) is the first-line treatment for the life-threatening allergic reaction known as anaphylaxis ^[20]. The most common anaphylactic reactions are induced by foods, insect stings and medications ^[21]. Adrenaline is both a hormone and a medication which plays an important role in the body’s “fight-or-flight” response (the acute stress response). It is used to treat anaphylaxis as it provides immediate symptomatic relief. It helps open up the airways, maintain heart function and raise blood pressure, reducing or reversing severe symptoms like throat swelling and difficulty in breathing ^[21].

Immunotherapy

Allergen immunotherapy is the last line of medications, also known as the closest “cure” for allergies. It is often recommended for patients whose symptoms cannot be controlled by medications, or those who require multiple medications to control their allergies. This immunotherapy involves regular administration of gradually increasing doses of the substance to which the person is allergic over several years. Treatment can be given as an injection, tablet, sprays or sublingual drops. The gradual increase of allergen causes the immune system to become less sensitive to the substance (desensitization), reducing symptoms during future exposures to the allergen, and possibly preventing new allergies.

Future developments

References