Ketotifen

Ketotifen, an antihistamine medication and a mast cell stabilizer, is most commonly sold as a salt with fumaric acid, ketotifen fumarate, and is available in two forms: it is used to treat allergic conjunctivitis; • in its oral form (tablets or syrup), as well as various mast cell and allergy disorders. Ketotifen ophthalmic solution (eye drops) relieves and prevents eye itchiness and/or irritation associated with most seasonal allergies. It starts working within minutes after administering the drops. The safety and effectiveness of ketotifen eye drops in children under three years of age have not been established, This blocking prevents the binding of histamine to these receptors and thus reduces the symptoms of histamine-mediated reactions, such as itching, sneezing, wheezing, and swelling. As a mast cell stabilizer to treat MCAS, oral ketotifen prevents the release of histamine and other inflammatory substances from mast cells, which are immune cells that react to allergens. helps reduce symptoms of conditions typically associated with mast cell activation. Ketotifen inhibits calcium influx into cells, reducing mast cell degranulation. The maximum antihistamine and mast cell stabilizing effect of oral ketotifen is achieved on long-term administration, and a period of at least 6-12 weeks is necessary for a maximum therapeutic effect to start. The sedation side effect decreases over time during such long-term administration, but the antihistamine and mast cell stabilizing properties persist even if administered for 12 months or longer. In the United States, the Food and Drug Administration (FDA) has not approved an oral formulation of ketotifen; however, oral ketotifen is available through compounding pharmacies with a prescription. In the UK, ketotifen is available as tablets and elixir (liquid). Oral ketotifen can be used as a long-term control medication for asthma and wheeze in children. It has been shown to improve asthma control by reducing the need for bronchodilators, decreasing symptoms, preventing exacerbations, and reducing the use of rescue oral steroids. Ketotifen is effective when used alone or in combination with other medications and serves as an alternative to inhaled therapy for asthma in children, especially for younger children who may have difficulty using inhalers. One small study in men found that the mean elimination half-life of oral ketotifen is 12 hours. Besides its anti-histaminic activity, it is also a functional leukotriene antagonist (a medication that blocks the action of leukotrienes, which are chemicals that cause inflammation and narrowing of the airways in some allergic and respiratory conditions) and a phosphodiesterase inhibitor (a medication that blocks the enzymes that regulate the levels of cAMP and cGMP, which are molecules that control blood vessel dilation and smooth muscle relaxation in the body). ==Contraindications==

The eye drops are contraindicated for individuals who have a known hypersensitivity to ketotifen or any other ingredient in the formulation, whereas drug-eluting contact lenses are contraindicated for those who experience irritation from wearing contact lenses. Eye drops are not recommended for use in children under three years of age, whereas drug-eluting contact lenses are not recommended for children under eleven years of age. (a group of rare disorders that occur when the body cannot make enough of a substance called heme, which is needed for red blood cells to carry oxygen; this causes a build-up of chemicals called porphyrins, which can damage the nerves and the skin). Unlike other histamines, ketotifen appears to be relatively safe in acute porphyria, still, caution should be taken. • epilepsy (a disorder causing recurrent seizures) - ketotifen may increase the risk of seizures, • pyloroduodenal obstruction • susceptibility to angle-closure glaucoma (a condition where the iris, the colored part of the eye, bulges and blocks the drainage of fluid from the eye, causing high pressure and damage to the optic nerve, which connects the eye to the brain), and • urinary retention (inability to urinate). Ketotifen safety when taken via the oral route (tablets or syrup) during pregnancy and lactation remains unknown; therefore, it is not recommended to use ketotifen orally during these periods until sufficient safety data becomes available. ==Side effects==

Common side effects of ophthalmic use are eye redness and swelling. Less common are eye discharge, eye discomfort, eye pain, hives, increased itching of eyes, and rash. Ophthalmic use of ketotifen may also cause burning, stinging, or itching of the eyes, blurred vision, or increased sensitivity to light. Systemic use of ketotifen may also cause abdominal pain, nausea, vomiting, constipation, diarrhea, headache, dizziness, or fatigue. In rare cases, systemic use of ketotifen may cause serious side effects such as anaphylaxis, liver dysfunction, blood disorders, or seizures. Systemic use of ketotifen may interact with other drugs that cause sedation, such as alcohol, antihistamines, opioids, benzodiazepines, or antidepressants. Systemic use of ketotifen may affect the results of some laboratory tests, such as skin tests for allergies or blood glucose levels. ==Overdose==

The symptoms of ketotifen overdose are dose-dependent and may vary from mild to severe. The onset of symptoms may be delayed for several hours after ingestion, and the duration of symptoms may last for more than 24 hours. The most common symptom of ketotifen overdose is significant sedation. Other symptoms may include confusion, disorientation, agitation, hallucinations, ataxia (impairment of voluntary muscle movement), tremor (involuntary regular muscle contraction), myoclonus (involuntary, irregular muscle twitch), nystagmus (dysfunction of eye movement), dysarthria (poor speech), and slurred speech. == Interactions ==

In systemic (oral) administration, ketotifen has the potential to enhance the effects of sedatives, hypnotics, antihistamines, and alcohol. Interactions have been observed between oral ketotifen and oral hypoglycemic agents, antihistamines, and medications with sedative properties. Oral ketotifen may interact with amphetamine and benzphetamine, which may decrease the activities of ketotifen. The concomitant use of oral ketotifen with amifampridine, bupropion, donepezil, and pitolisant is not recommended. In rare instances, patients who have been administered oral ketotifen with oral antidiabetic agents have exhibited a reversible decrease in thrombocyte count. As such, it is recommended to monitor thrombocyte counts in patients who are concurrently taking oral antidiabetic agents. ==Pharmacology==

Pharmacodynamics Ketotifen is a selective antihistamine – that is, an inverse agonist of the histamine H1 receptor – and mast cell stabilizer. By preventing the degranulation of mast cells, ketotifen inhibits the release of inflammatory mediators such as histamine and leukotrienes, which are implicated in allergic reactions. However, at the dosages in which it is typically used clinically, both the anticholinergic and antiserotonergic activity of ketotifen are said not to be appreciable. Ketotifen is a lipophilic compound that can cross the blood–brain barrier and exert central nervous system effects, such as sedation, Sedating antihistamines showed occupancies of 50 to 100%, with ketotifen having one of the highest occupancies. Ketotifen acts as a mast cell stabilizer by preventing the degranulation and release of histamine and other inflammatory mediators, such as leukotrienes, Ketotifen has a dual mode of action as an antihistamine and a mast cell stabilizer, which makes it effective in the prophylaxis and treatment of various allergic and respiratory conditions, such as asthma, allergic rhinitis, conjunctivitis, There is no academic consensus or the second generations of antihistamine drugs; the classification can vary depending on the criteria used and the context of the study, Ketotifen is a tricyclic, benzocycloheptene-based compound with chemical structures similar to first-generation antihistamines such as azatadine, cyproheptadine, chlorpheniramine, and diphenhydramine, and other compounds with antihistamine properties such as pizotifen. The sedative effects of ketotifen are also a reason for differences in classification. First-generation antihistamines are well known for their sedating side effects due to their ability to penetrate the blood–brain barrier. While ketotifen has some sedative properties, it is generally considered to have a milder sedative effect compared to traditional first-generation antihistamines, Pharmacokinetics Ketotifen has an average elimination half-life ranging from 3 to 22hours in different studies. The drug is extensively metabolized in the liver by oxidation and conjugation, and the metabolites are excreted in the urine and feces. The bioavailability of oral ketotifen is about 50% due to hepatic first-pass metabolism. Peak plasma concentration is reached in about 2 to 4 hours. The pharmacokinetics of ketotifen are not significantly affected by age, gender, or renal impairment, but may be altered by hepatic impairment or concomitant use of other drugs. Ketotifen, like other antihistamines, is mainly metabolized by the cytochrome P450 (CYP) enzymes, especially CYP3A4 in the liver. The CYP enzymes are responsible for the oxidation and demethylation of ketotifen, producing the major metabolites norketotifen and 10-hydroxyketotifen. Norketotifen is pharmacologically active and has a similar potency as ketotifen, while 10-hydroxyketotifen is inactive. The metabolites are then conjugated with glucuronic acid or sulfate and excreted in the urine and feces. ==Chemistry==

A close analogue of ketotifen is pizotifen, which is a tricyclic (having three rings of atoms), benzocycloheptene-based compound with antihistamine properties: the only difference between the structures of the compounds is that the ketotifen molecule has an oxygen atom that pizotifen molecule lacks—ketotifen contains a carbonyl group (C=O) in the central (7-membered) ring while pizotifen contains a methylene group (-CH2-) in that position. In both ketotifen and pizotifen, the spatial restriction and reduced degrees of freedom caused by the rings enable optimal binding to H1 receptors by providing shape complementarity and facilitating specific interactions with amino acid residues within the receptor's binding site, which plays a role in the ability of both drugs to effectively bind and modulate H1 receptors, thereby exerting its antihistamine effects. == History ==

Ketotifen was patented in 1970 and came into medical use in 1976. Ketotifen was developed and patented by Sandoz Pharmaceuticals (a part of Novartis), a Swiss company. Ketotifen was approved for medical use in Canada in December 1990. A contact lens with ketotifen was approved for medical use in the United States in 2022. == Society and culture ==

Economics Ketotifen is available as a generic drug. In October 2006, the FDA approved the switch of Zaditor from prescription to over-the-counter (OTC) status, and it became available OTC in January 2007. Outside the United States, oral ketotifen is available as a generic in countries where it is approved, including Canada, EU member states, and the United Kingdom. In the United States, ketotifen fumarate ophthalmic solution is marketed under brand name Zaditor, which is owned by Alcon Inc., a Swiss-American pharmaceutical company. ==Research==

Anatomy Human mast cell heterogeneity (diversity) significantly impacts the efficacy of ketotifen in preventing mediator release (mast cell activation). In experiments, ketotifen inhibits mast cells from lung and tonsillar tissues when stimulated via an IgE-dependent histamine release mechanism. However, neither ketotifen nor disodium cromoglycate, another mast cell stabilizer, inhibited mediator release from skin mast cells that were unresponsive to these stabilizers. Such patterns of mast cell activation suggest the existence of different types of mast cells across various tissuesa topic of ongoing research. The potential future applications of norketotifen are researched by Emergo Therapeutics, a US company. Conditions Increased appetite and weight gain The underlying mechanisms of why ketotifen (similarly to other antihistamine drugs such as astemizole and azelastine) Studies on mice suggest that caffeine may prevent weight gain induced by ketotifen, but this has not been confirmed in human subjects. == References ==