Ketotifen fumarate is an H1 antihistamine and mast cell stabilizer used in treatment of allergies and asthma orally and for allergic symptoms and allergic conjunctivitis in ophthalmic form. Ketotifen is also known for its effect of up-regulating the beta-2 adrenergic receptors, and can for that reason be combined with clenbuterol for treatment of especially severe asthma. Ketotifen inhibits phosphodiesterase, a chemical involved in the homeostatic feedback loop of beta-2 adrenergic activity.
Castillo writes the following about ketotifen’s effect on beta-2 adrenergic receptor expression and the role of phosphodiesterase in asthma:
In this study we observed that asthmatics had less methyltransferase activity and greater phosphodiesterase activity than healthy individuals. These enzymatic activities were nearer to values obtained in healthy individuals when we preincubated cells with ketotifen. The modulator effect of this drug on these two enzymes permits, on the one hand, to re-establish the beta-receptor numbers expressed on the membrane, and on the other hand, to inhibit mediator secretion provoked by antigenic stimulus. With its action on adenylate cyclase and phosphodiesterase activities, it allows cAMP intracellular accumulation and hinders the secretory process. Through its action on methyltransferase activity, it is responsible for the normalization of beta-receptor expression observed in asthmatic patients treated with ketotifen.
Raajimakers provides further analysis of ketotifen’s important action on beta-2 adrenergic receptors via phosphodiesterase inhibition; the mode of action was initially presumed to be through leukotriene antagonism (leukotrienes are fatty molecules involved in the immune cascade that are thought to contribute to inflammatory asthma):
Adrenoceptor (sub)populations (alpha 1, beta and beta 1/beta 2 ratio) in human lung tissue were characterized by means of radioligand binding assays. Lung tissue specimens for these assays were obtained at thoracotomy from normal individuals and COLD patients. The patients were not receiving therapy known to influence adrenoceptor characteristics. In COLD patients, the number of alpha 1-adrenoceptors appeared to be markedly enhanced while the relative amount of beta 2-adrenoceptors was decreased. Furthermore, some adrenoceptors seemed to be correlated to pulmonary function both in the normal individuals and COLD patients. In-vitro modulation with disodium cromoglycate and ketotifen revealed therapeutic possibilities for these substances based on other pharmacological mechanisms than hitherto assumed.
Ketotifen’s multiple actions mean that further research will likely yield further uses for the versatile research chemical, as Klooker’s analysis of data implies:
Ketotifen but not placebo increased the threshold for discomfort in patients with IBS with visceral hypersensitivity. This effect was not observed in normosensitive patients with IBS. Ketotifen significantly decreased abdominal pain and other IBS symptoms and improved quality of life. The number of mast cells in rectal biopsies and spontaneous release of tryptase were lower in patients with IBS than in healthy volunteers. Spontaneous release of histamine was mostly undetectable but was slightly increased in patients with IBS compared with healthy volunteers. Histamine and tryptase release were not altered by ketotifen. CONCLUSIONS: This study shows that ketotifen increases the threshold for discomfort in patients with IBS with visceral hypersensitivity, reduces IBS symptoms and improves health-related quality of life. Whether this effect is secondary to the mast cell stabilising properties of ketotifen or H(1) receptor antagonism remains to be further investigated.
Through robust effect, when co-administered with B2-adrenergic down-regulators, ketotifen successfully maintains cellular sensitivity; when administered independently, it actually increases B2-adrenergic density:
We examined the effect of ketotifen on the down-regulation of beta-adrenoceptors in guinea pig lung chronically treated with terbutaline. There was a significant decrease in the density of beta-adrenoceptors following chronic administration of terbutaline. Ketotifen prevented the decrease in beta-adrenoceptor density induced by terbutaline in a dose-dependent fashion; ketotifen alone, also increased the density of beta-adrenoceptors. However, neither ketotifen nor terbutaline significantly changed the KD values in either group. These findings suggest that ketotifen might be valuable when beta-agonists are administered for long term treatment in asthmatic patients.
 Castillo JG, Oehling A, Gamboa PM. Mechanism of ketotifen action in hypersensitivity reactions. Its effect on cellular enzymatic activities. J Investig Allergol Clin Immunol. 1991 Oct;1(5):315-23.
 Raaijmakers JA, Wassink GA, Kreukniet J, Terpstra GK. Adrenoceptors in lung tissue: characterization, modulation and relations with pulmonary function. Eur J Respir Dis Suppl. 1984;135:215-20.
 Klooker TK, Braak B, Koopman KE, Welting O, Wouters MM, van der Heide S, Schemann M, Bischoff SC, van den Wijngaard RM, Boeckxstaens GE. The mast cell stabiliser ketotifen decreases visceral hypersensitivity and improves intestinal symptoms in patients with irritable bowel syndrome. Gut. 2010 Sep;59(9):1213-21.
 Koshino T, Agrawal DK, Townley TA, Townley RG. Ketotifen prevents terbutaline-induced down-regulation of beta-adrenoceptors in guinea pig lung. Biochem Biophys Res Commun. 1988 May 16;152(3):1221-7.
*The latter article is intended for educational / informational purposes only. THIS PRODUCT IS INTENDED AS A RESEARCH CHEMICAL ONLY. This designation allows the use of research chemicals strictly for in vitro testing and laboratory experimentation only. Bodily introduction of any kind into humans or animals is strictly forbidden by law.